Jichi Medical Research Overview 2015

解剖学

Division/Department:

Division of Anatomy, Bio-imaging and Neuro-cell Science

Theme of research:

Molecular mechanism of the morphological change of the living cell during cell differentiation and migration.

Name of main researcher, title, and e-mail address:

Yasuko Noda, M.D. & Ph.D., Professor and chairman, [email protected]

Brief explanation of research activity:

We are interested in the molecular mechanism of the dynamics of intracellular organelles and effects on the morphology of the cell. We conduct real-time observation of membrane-associated molecules involving intracellular organelles and cytoskeletal proteins, using double, triple, or quadruple fluorescent labeling in live cell imaging. We analyze dynamics in living cultured cells with a high-resolution deconvolution fluorescence microscopy system.

組織学


Division of Histology and Cell Biology, Department of Anatomy

Theme of research:

Cellular, Structural and Functional Biology of the Organ


Takashi Yashiro, MD and PhD, Professor, [email protected] Ken Fujiwara. PhD, Assistant Professor, [email protected] Takehiro Tsukada. PhD, Research Professor, [email protected] Morio Azuma. PhD, Research Professor, [email protected]


Various sorts of cells are harmonized to provide integrated responses of the tissue in organism. This coordination cannot be achieved without cells recognize specific microenvironment they have laid, through cues issued from cell-cell and cell-matrix adhesion. Our interests base on a question how functions of endocrine cells are modified by the microenviromental cues, in addition the humoral and neural controls, especially for the anterior pituitary cells. This “microenvironment” might play important roles on the cell differentiation from the stem cell, tumor genesis and regeneration of the organ or tissue. In the pituitary gland, we are clarifying mechanism that makes the specific cell

attachment, and functional role of the specific cell attachment by studying : 1) cell adhesion molecules using techniques including immunohistochemistry, in situ hybridization and immunoelectron microscopy, as well as possible “outside-in signal transduction” by the molecules, 2) cell type specific sugar chain expression on cell membrane, 3) metricrine modulation of hormone-producing cells raised by cell-extracellular matrix adhesion, 4) cell communications through gap junctions and 4) juxtacrine modulation of hormone gene expression by specific cell attachment, utilizing a technique of reporter gene transfection which enables us to observe gene expression in live cells.

法医学


Division of Forensic Medicine, Department of Anatomy

Theme of research:

Study on fluorescent granular perithelial(FGP)cell.


Prof. Atsushi Sakamoto ,[email protected]


FGP cells containing auto-fluorescent granules are reported to be located between blood vessels and neural tissue in cerebral cortex by Mato et.al. The FGP cells are expected to play an important role on the blood brain barrier(BBB), because these cells phagocyte blood-born HRP as well as scavenge wastes/foreign substance in the brain tissue and also

show the presence of macrophage lineage receptors such as MHC-Ⅱ, which suggests an

immunological function of FGP cells in the BBB. So we are studying the further distribution and function of FGP cells in the central nervous system.

生物物理学


Division of Biophysics, Department of Physiology

Theme of research:

Study on mechanisms of protein allostery


Naoya Shibayama, Professor, [email protected]


Allostery, the process by which proteins change their shape upon binding small molecules or ions, is used in many biological processes. Despite its importance, mechanisms of allostery are still poorly understood. The hemoglobin molecule offers the best experimental system for the study of mechanisms of allostery. To investigate the molecular events that occur in hemoglobin, we have used a variety of approaches including X-ray crystallography, neutron crystallography, various spectroscopic techniques, site-directed metal-substitution, chemical cross-linking, sol-gel entrapment (to lock in the hemoglobin conformation during measurement) and functional analysis both in solution in crystals.

神経脳生理学


Division of Brain and Neurophysiology, Department of Physiology

Theme of research:

Neural mechanisms of stress, emotion and social behaviour


Yuki Takayanagi, Lecturer, [email protected]

Masahide Yoshida, Assistant Professor, [email protected]

Tatsushi Onaka, Professor, [email protected]


Stress, obesity, and social relationship largely affect clinical course of various diseases. However,

neural mechanisms of these factors remain unclear. Both genetic and environmental factors affect

stress responses, emotion-related behaviour or social behaviour. We have been investigating

neural mechanisms of stress, emotion or social behaviour by using various kinds of methods

including molecular genetics.

Current research topics:

1) Neural and molecular mechanisms of social behaviour

2) Neural and molecular mechanisms of acute or chronic stress

3) Neural and molecular mechanisms of interactions among stress, energy metabolisms and

social behaviour

4) Neural and molecular mechanisms of endogenous anti-stress, anti-obesity and pro-social

systems

References

Science 34:333-336, 2015.

Endocrinology 155:2996-3004, 2014.

J Neuroendocrinol 25: 455-465, 2013.


Nature 464: 413-417, 2010.

Trends Endocrin Met 21: 287-293, 2010.

J Neurosci 29: 2259-2271, 2009.

J Clin Invest 118: 4014–4024, 2008.

神経脳生理学


Division of Brain and Neurophysiology, Department of Physiology

Theme of research:

Physiological functions of vasopressin and oxytocin in the central nervous system


Masahide Yoshida, Assistant Professor, [email protected]

Yuki Takayanagi, Lecturer, [email protected]

Tatsushi Onaka, Professor, [email protected]


Vasopressin and oxytocin are synthesized mainly in the hypothalamic neurons and released not

only from their axonal terminals but also from dendrites or cell bodies in the hypothalamus.

Central administration of vasopressin or oxytocin affects emotional or social behaviour. Receptors

for vasopressin or oxytocin are distributed in the brain. Vasopressin or oxytocin receptor-deficient

mice show abnormal emotional or social behavior. However, neural and molecular mechanisms of

the actions by vasopressin or oxytocin remain unclear.

Current research topics:

1) Physiological roles of vasopressin or oxytocin within the hypothalamus

2) Neural and molecular mechanisms of developmental actions by vasopressin or oxytocin

3) Neural and molecular mechanisms of dendritic vasopressin or oxytocin release

References

Endocrinology 155:2996-3004, 2014.





Nature 464: 413-417, 2010.

J Neurosci 29: 2259-2271, 2009.

Horm Behav 55: 434-441, 2009.

J Clin Invest 118: 4014–4024, 2008.

Proc Natl Acad Sci USA 102: 16096-16101, 2005.

統合生理学

Department/Division:

Physiology/Integrative physiology

Theme of research:

Ghrelin regulates insulin release and blood glucose level: physiological significance and therapeutic potential


Katsuya Dezaki, Tomoyuki Kurashina, Masanobu Taguchi, Rauza S. Rita, Masanori Nakata, Toshihiko Yada Principal Investigator: Katsuya Dezaki, Associate Professor, [email protected]

Brief explanation of research activity: Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor

(GHS-R), is produced predominantly in the stomach and potently stimulates GH release and feeding. Our studies have established ghrelin as a novel islet hormone that inhibits insulin release and thereby upwardly regulates blood glucose, which was evidenced by the following findings.

Ghrelin and GHS-R are expressed in pancreatic islets [1,2], and ghrelin is released into the pancreatic vein [3]. Ghrelin immunoneutralization and GHS-R antagonists augment glucose-stimulated insulin secretion (GSIS) from isolated pancreas and islets [2]. GHS-R blockade increases plasma insulin concentration in gastrectomized and normal rats similarly [3]. Ghrelin acts on islet -cells and attenuates glucose-induced cAMP production, which drives activation of voltage-dependent Kv channels and suppression of the glucose-induced [Ca2+]i increases and insulin release [4,5]. GSIS is greater in ghrelin-deficient than wild-type mice [3]. Thus, pharmacological, immunological and genetic blockade of ghrelin or ghrelin action in pancreatic islets all markedly enhance GSIS. Moreover, ghrelin deficiency enhances insulin release and prevents the high-fat diet-induced impaired glucose tolerance [3]. Ghrelin also attenuates glucagon-like peptide-1 (GLP-1)-potentiated insulin release by suppression of cAMP production in -cells [6]. Low doses of GLP-1 agonist and Kv2.1 channel blocker synergistically stimulate insulin release and lower blood glucose in type 2 diabetic mice [7].

Thus, ghrelin inhibits glucose-induced and GLP-1-potentiated insulin release, and manipulation of insulinostatic function of ghrelin in islets could optimize insulin release to meet the systemic demand, providing a novel therapeutic tool to treat type 2 diabetes [8,9]. We aim to fully elucidate the action mechanisms of ghrelin, and to develop a novel ghrelin-based treatment for type 2 diabetes and possibly metabolic syndrome.

Surgery is the main therapy in the patients with gastric cancer, but postoperative dysfunctions such as impaired food intake and weight loss lead to a difficulty in recovery of the quality of life. We aim to elucidate the mechanism of postoperative dysfunctions, and to evaluate its intervention using Kampo medicine.

[1] Diabetes 51:124-129, 2002, [2] Diabetes 53:3142-3151, 2004, [3] Diabetes 55:3486-3493, 2006, [4] Diabetes 56:2319-2327, 2007, [5] Diabetes 60:2315-2324, 2011, [6] FEBS Lett 586:2555-2562, 2012, [7] Endocrinology 156:114-123, 2015, [8] Methods Enzymol 514:317-331, 2012, [9] Diabetes Obes Metab 1:111-117, 2014

統合生理学



Theme of research:

The hypothalamic and vagal afferent neurons senses systemic signals to regulate feeding and body’s functions


Yusaku Iwasaki, Shigetomo Suyama, Parmila Kumari, Masanori Nakata, Katsuya Dezaki, Kenichi Katsurada, Eisuke Takano, Toshihiko Yada

Principal Investigator: Toshihiko Yada, Professor, [email protected]


The hypothalamus receives peripheral metabolic signals that enter the brain through the blood-brain barrier (BBB), and regulates feeding behavior and energy metabolism. The orexigenic neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC), the first order center, are directly activated by low glucose [1], ghrelin [2], orexin [3] and PACAP [4], while inhibited by leptin [5], insulin [6] and GABA [7]. NPY neurons integrate these orexigenic and anorexigenic signals: leptin counteracts the ghrelin-induced stimulation of NPY neurons and feeding [5]. Type 2 diabetic GK rats display hyperphagia and visceral obesity due to leptin resistance and dysfunction of ARC NPY neurons [8]. We now aim to elucidate the neural circuit that relays the ARC to the paraventricular nucleus (PVN), the second order center, and to feeding behavior. Nesfatin-1 [9], BDNF [10] and GLP-1 [11] in the PVN play a key role in suppressing food intake.

The vagal afferent nerves sense the peripheral information and convey these signals to the brain, resulting in regulation of feeding and metabolism. We established a new method of analyzing the vagal afferent nodose ganglion neuron (NGN). Cytosolic Ca2+ concentrations and membrane currents in single NGNs isolated from rodents are measured by fluorescence imaging and patch clamp technique, followed by immunocytochemical identification of their neurotransmitters. We have found that the vagal afferent NGNs directly sense gastrointestinal/pancreatic hormones, GLP-1 [12], nesfatin-1 [13], peptide YY3-36 [14], insulin [15], glucagon [16] and pancreatic polypeptide [14], thereby conveying the signals to the brain to regulate feeding. Recently, we have found that peripheral administration of oxytocin reduces feeding and ameliorates obesity via direct interaction with vagal afferents [17,18]. We are studying the role of the vagal afferent-mediated peripheral-central network in physiological regulation of feeding, metabolism and brain functions. Dysfunction of the vagal afferents may be implicated in the metabolic and neural diseases including feeding disorders, obesity, diabetes, blood pressure, depression and Alzheimer disease.

[1] Neurosci Lett 264:113-6, 1999, [2] Diabetes 52:948-56, 2003, [3] Eur J Neurosci 19,1524-34, 2004, [4] Neruosci Lett 370:252-6, 2004, [5] Endocrinology 148; 2251-63, 2007, [6] Aging 3(11):1092-7, 2011, [7] Neuroreport 16:897-901, 2005, [9] Cell Metabolism 10: 355-65, 2009, [10] J Neuroendocrinology, 22(9):987-95, 2010, [11] BBRC 451(2):276-81, 2014, [8] J Neuroendocrinol 18:748-756, 2006, [12] Auton Neurosci 102:39-44, 2002, [13] BBRC 390:958-962, 2009, [14] Neuropeptides 47:19-23, 2013, [15] PLOS ONE 8(6):e67198, [16] BBRC 456(3):727-32, 2015, [17] Aging 3(12):1169-77, 2011, [18] Am J Physiol Regul Integr Comp Physiol 308(5):R360-9, 2015

統合生理学



Theme of research:

Network and therapeutic potential of nesfatin-1 and oxytocin to treat obesity syndrome and psychiatric disorders


Toshihiko Yada, Putra Santoso, Yifei Yang, Zesemdorj Otgon-Uul, Parmila Kumari, Kenichi Katsurada, Yusaku Iwasaki, Katuya Dezaki, Masanori Nakata Principal Investigator: Yuko Maejima, Assistant professor, [email protected]


To develop an effective treatment of obesity and metabolic syndrome, it is essential to clarify the regulation of feeding and energy metabolism. We discovered a novel neuro-circuit operated by new and clasic neuropeptides, nesfatin-1 (Nesf) and oxytocin (Oxt), in the hypothalamic paraventricular nucleus (PVN). The PVN Nesf neurons induce oxytocinergic signaling to proopiomelanocortin (POMC) neurons located in the arcuate nucleus (ARC) [1] and in the brain stem nucleus tractus solitarius (NTS) [2]. The PVN Nesf is regulated by leptin and mediates the anorexigenicic effect of leptin [3]. Nesf in PVN is activated by meal [4], the neural projection from the ARC [5], and glucose and insulin [6]. Nesf neurons are also activated by stressors and in turn provoke CRH-ACTH-glucocorticoid and serotonin pathways, the stress/psychiatric systems [7]. Furthermore, the PVN Nesf/NUCB2 mRNA expression is raised in light phase (LP), which is tightly linked to feeding suppression at LP. We have demonstrated that diurnal Nesf/NUCB2 rhythm drives circadian feeding rhythm [8].

Nesf is also localized in the peripheral tissues and in the circulation. We found that both Nesf and Oxt, when injected peripherally, also inhibit feeding [9,10]. Peripheral Oxt treatment corrects obesity and metabolic syndrome [10]. These effects of peripheral Oxt is largely mediated by its direct activation of the vagal afferent nerve and resultant signaling to the brain [11]. Nasal and IP administrations of Oxt similarly inhibit feeding [12]. Our goal is to clarify (patho)physiological roles of Nesf and Oxt in the regulation of feeding and psychiatric behaviors, and to invent an Oxt-based effective and safe treatment of obesity.

[1] FEBS Letters 588:4404-4412, 2014, [2] Cell Metabolism 10:355-365, 2009, [3] Biochem Biophys Res Commun 456:913-918, 2015, [5] Endocrinology 149:1295-1301, 2008, [5] NeuroReport 25:1453-1458, 2014, [6] Biochem Biophys Res Commun 420:811-815, 2012, [7] Aging 2:775-784, 2010, [8] Biochem Biophys Res Commun 434:434-438, 2013, [9] Endocrinology 150:662-671, 2009, [10] Aging 3:1169-1177, 2011, [11] Am J Physiol 308:R360-R369, 2015, [12] Neuroendocrinology 101:35-44, 2015.

統合生理学


Physiology / Integrative Physiology

Theme of research:

Elucidating the mechanisms of circadian rhythms of feeding and metabolism


Masanori Nakata, Rai Wang, Yifei Yang, Toshihiko Yada Principal Investigator: Masanori Nakata, associate professor, [email protected]


The circadian system in mammals is organized by a network of circadian oscillators. The master clock is located in the hypothalamic suprachiasmatic nucleus (SCN), in which approximately 20,000 neurons are synchronized in their activities. Partly under the influence and partly independently of the SCN master clock, circadian oscillators are present in other brain areas and peripheral organs, which are thought to be implicated in the circadian rhythms of physiological functions, including the rhythms of feeding and hormone release.

We intend to demonstrate that the impairment of circadian rhythms induced by environment factors induces feeding disorder, metabolic syndrome and depression, and to elucidate the underlying mechanisms.

PVN is considered a regulatory center for feeding and circadian activities of hormone release and autonomic nerve. Nucleobindin2 (NUCB2) and its processing product nesfatin-1 (NUCB2/nesfatin-1) are localized in the hypothalamic paraventricular nucleus (PVN) and implicated in regulation of feeding. We reported that NUCB2 mRNA expression in the PVN rises during early light phase (LP) in parallel with suppression of food intake [1]. Furthermore, the rise of PVN NUCB2 mRNA during LP was blunted in obese rats which exhibited LP-preferential hyperphagia. These results suggested that the circadian rhythm of PVN NUCB2 mRNA expression regulates circadian pattern of feeding. In addition, the function of nesfatin-1/NUCB2 neuron in PVN is regulated by meal-induced factors such as high glucose, insulin and leptin [2,3]. Nesaftin-1/NUCB2 may play a role in coupling energy metabolism and circadian rhythms. Using PVN specific conditional NUCB2 knockout mice and knockdown mice expressing NUCB2 shRNA by AAV vector, we aim to further explore the function of NUCB2.

[1] Sedbazar U et al. Biochem Biophys Res Commun. 434:434-438, 2013. [2] Gantulga D et al. Biochem Biophys Res Commun. 420:811-815, 2012. [3] Gantulga D et al. Biochem Biophys Res Commun. 456:913-918, 2014

構造生化学


Division of Structural Biochemistry, Department of Biochemistry

Theme of research:

Studies on biosynthesis of selenocysteine, selenoproteins and the related molecules


Jitsuhiro Matsugi, Associate Professor, [email protected]


In many cases, selenoproteins function as redox protein like glutathione peroxidases and thioredoxin reductases and they contain selenocysteine (Sec) in the catalytic center. Thus, it is thought that selenoproteins are strongly associated with tumorigenesis, aging and other stress-related phenomena. For biosynthesize selenoproteins, specific mechanisms are employed in its translational system, such as its assigned codon, unique tRNA, elongation factor and cis-element in the mRNA. Since it has been confirmed that selenoproteins are essential for higher animals, Sec is referred to the 21th amino acid. In my research, the structural feature of the molecules necessary for biosynthesis of selenoprotein is investigated using biochemical techniques.

構造生化学



Theme of research:

Molecular mechanism of high-fidelity chromosome transmission


Satoshi Ohta, Ph.D., Research Associate, [email protected]


My general interests involve understanding the regulation of cellular growth control. The aim is to understand how a tumorigenic cell growth differs from a normal one. My research focuses on the role of NF-HEV/IL-33 in cell growth and oncogenic signaling pathway. Although NF-HEV/IL-33 is reported to be localized in nucleus, currently, the nuclear function of IL-33 is not well understood. In addition, I have been involved in a collaboration searching for novel tumor makers from colorectal cancer patients.

構造生化学



Theme of research:

Signaling crosstalk of proto-oncogene’s products and tumor suppressors


Kenji Tago, Ph.D., Assistant Prof., [email protected]


Disruption/silencing of tumor suppressing signals and/or hyper-activation of cell proliferative signals are known to be the triggers for tumorigenesis. We are focusing on the signaling crosstalk between proto-oncogene’s products including Ras and Myc, and tumor suppressor Arf and p53. We identified an RNA helicase DDX5 as a novel interacting protein of Arf tumor suppressor, and found that Arf suppresses the function of DDX5 and this seems to be a mechanism of Arf-induced tumor suppressive signals. We are also interested in the function of novel nuclear-cytosolic small GTPase �NKi-Ras. Our current observations suggest that NKi-Ras seems to harbor the critical roles in tumorigenesis. We recently identified several interacting proteins of �NKi-Ras, and now attempt to clarify their functions.

機能生化学


Division of Functional Biochemistry, Department of Biochemistry

Theme of research:

Comprehensive proteomic analysis of mammalian mitochondrial membrane proteins


Hitoshi Endo, Professor, [email protected] Katsumi Kasashima, Assistant Professor, [email protected] Kenji Kuroiwa, Assistant Professor, [email protected]


Mitochondria is an eukaryotic organelle that plays crucial roles in several cellular process, including ATP production, fatty acid oxidation, apoptosis, calcium homeostasis and reactive oxygen species (ROS) signaling and is closely related to human diseases, such as metabolic syndrome, neuromuscular disease and aging. Although the number of mammalian mitochondrial protein is predicted to be about 2,000, they are not totally distinguished. To understand the molecular mechanisms of mitochondrial functions, we performed a comprehensive proteomic analysis focusing on mitochondrial membrane that provides a space for most of important mitochondrial functions described above. To date, we have identified 171 proteins from purified mitochondrial membrane fraction of HeLa cells by 2D-electrophoresis and LC-MS/MS. Among them, we selected 13 novel proteins, which have no previous information about the function and localization. Eight proteins were subcloned and confirmed to localize to mitochondria.We are now investigating precise functions of the newly identified mitochondrial membrane proteins by biochemical and molecular biological approaches.

機能生化学



Theme of research:

Function analysis of mitochondrial protein, PHBs


Katsumi Kasashima, Assistant Professor, [email protected] Kenji Kuroiwa, Assistant Professor, [email protected] Hitoshi Endo, Professor, [email protected]


Prohibitins (PHBs), including PHB1 and PHB2, are evolutionally conserved and have pleiotropic cellular functions, such as apoptosis, regulation of cell cycle, signal transduction, and aging. PHB2 is known to act as transcriptional repressor in nucleus. We identified PHB2’s mitochondrial functions in anti-apoptosis and mitochondrial morphology for the first time (Kasashima et al, 2006), and also observed that PHB2 shuttles between mitochondria and nucleus. Showing that PHBs function differently in both organelles, and it is suggested that PHBs mediate nuclear-mitochondrial interaction. We are now investigating the novel PHBs functions in mitochondria and the relation with the functions in nucleus.

機能生化学



Theme of research:

RNA processing and gene expression


Eiji Sakashita, Assistant Professor, [email protected] Katsumi Kasashima, Assistant Professor, [email protected] Kaoru Tominaga, Associate Professor, [email protected] Hitoshi Endo, Professor, [email protected]


Our laboratory studies the mechanisms of gene expression at the posttranscriptional level. One is the molecular details of how tissue-specific alternative splicing, i.e., inclusion or skipping of a variably spliced exon, occurs in mammalian cells. To investigate the mechanism of alternative splicing, we work on human mitochondrial ATP synthase gamma subunit gene (F1 gamma) whose alternative exon 9 is excluded only in heart and skeletal muscle as a tissue-specific model substrate. We also investigate intracellular movements of splicing factors including a subset of SR protein family, in response to UV- and heat shock-induced stress signals. Another area is to investigate the cellular role of developmentally-regulated RNA-binding protein (Drb1), newly cloned in our laboratory. Drb1 gene is specifically expressed in fetal rat brain and gradually reduced during development. Our current goals are (i) to identify RNA target(s); (ii) to understand the mechanism of regulation; (iii) to make Drb1 knockout mice and check the phenotype.

機能生化学



Theme of research:

Chromatin regulation for cell growth control and DNA damage repair


Kaoru Tominaga, Associate Professor, [email protected] Hitoshi Endo, Professor, [email protected]


Chromatin is composed of units of DNA and histone proteins and maintains the proper three-dimensional structure of DNA. Chromatin structure needs to be modulated in many cellular processes such as transcription, DNA replication, and DNA repair and proper control of chromatin structure is critical for regulation of cellular activities. Chromatin binding protein MRG15 was originally isolated through the studies of cellular senescence. It has been shown that MRG15 regulates chromatin through making complexes with histone acetyltransferases (HATs) and histone deacetylases (HDACs). Our studies using Mrg15 knockout mice show that MRG15 is important for cell growth control including neural stem cells (NSCs) and for DNA damage repair. We are currently investigating the molecular mechanism(s) of MRG15 action in these cellular processes using Mrg15 deficient mouse embryonic fibroblasts (MEFs) and NSCs. Our studies should help to increase our knowledge about the importance of chromatin modification and epigenetic regulation as well as the molecular mechanism of diseases caused by dysregulation of chromatin such as cancer and neurological disorders.

病態生化学


Division of Medical Biochemistry/Department of Biochemistry

Theme of research:

・Development of next generation gene therapy by genome editing

・Pathophysiological roles of forkhead box transcriptional factor


Tsukasa Ohmori MD,PhD,Associate Professor, E-mail: [email protected]


1) The current types of gene therapy for an inherited disorder mainly utilize techniques to

ectopically express a normal gene by a vector, while leaving the abnormal somatic gene as it

is. An ideal gene therapy would “repair” the abnormal gene at the genomic DNA level. As

genome-editing technologies such as CRISPR/Cas9 systems have been significantly

improved, future applications of these technologies are anticipated. We are going to establish

technologies to treat patient genetic abnormalities by removing the abnormal gene and

replacing it with a normal gene, as a next generation treatment for inherited disorders

including hemophilia and severe immunodeficiency.

2) Forkhead box(FOX) proteins are a family of transcriptional factors to regulate cell growth

and differentiation. We identified a FOX protein as a downstream target of the cytoskeletal

protein Vinculin in hematopoietic stem cells by microarray analysis. We generated

conditional gene-deficient mice, and are now investigating the (patho)physiological roles of

the FOX protein in lung, heart, and blood cells.

細菌学


Division of Bacteriology, Department of Infection and Immunity

Theme of research:

Pathogenicity and antibiotic resistance of clinical bacteria; Development of novel

antibacterial agents targeting H. Pylori; Infection control science


Longzhu Cui, Professor, [email protected]


1) Pathogenicity and antibiotic resistance of staphylococcal species

a) We recently reported a prolonged persistent staphylococcal infection, the worst

case of staphylococcal infections, was due to the infection by a strain that

repeatedly reverts its half genome (Flip-Flop inversion), which switches bacterial

phenotype and generate heterogeneous cell population (Cui et al. PNAS 2012

p9686). Currently, we are expanding this finding into revealing the nature of

heterogeneity, one of the longest standing mysteries in bacterial physiology.

b) Our research on the antibiotic resistance of Staphylococcal species focuses on

uncovering mechanism of resistance against vancomycin, teicoplanin, linezolid

and daptomycin, and for the highly methicillin-resistant MRSA.

2) We also research on antibiotic resistance of opportunistic pathogens including K.

pneumoniae, P. aeruginosa and A. baumannii.

3) Development of novel antibacterial agents

We previously found out some novel compounds that have species-specific

bactericidal activity against Helicobacter pylori. We are now evaluating these

compounds toward drug development.

4) Infection control science

In collaboration with infection control team, our group manages infection control in

university teaching hospital by combining basic research and laboratory

surveillance.

ウイルス学


Division of Virology, Department of Infection and Immunity

Theme of research:

Molecular epidemiological and molecular biological studies on hepatitis viruses


Hiroaki Okamoto, Professor, [email protected] Masaharu Takahashi, Assistant Professor, [email protected] Shigeo Nagashima, Assistant Professor, [email protected] Tominari Kobayashi, Research Assistant, [email protected]


Our research projects, now in progress, are as follows: 1. Studies on genomic organization, genomic mutation and pathogenesis of hepatitis

viruses including HAV, HBV, HCV, HDV, and HEV as well as Torque teno viruses and related viruses

2. Studies on viral replication using cell culture systems 3. Development of methods for serological diagnosis of acute and chronic liver diseases 4. Development of methods for genomic diagnosis of acute and chronic liver diseases 5. Phylogenetic analyses and development of methods for genotyping of various hepatitis

viruses 6. Molecular epidemiological studies on hepatitis virus infections for elucidating

infectious sources and transmission routes and for developing preventive measures 7. Investigation of the prevalence of hepatitis virus infections among various populations

in Asian countries including Mongolia, China, Nepal, Vietnam, the Philippines, and Indonesia.

8. Identification and characterization of novel viruses related to diseases of unknown etiology

Details of our research activities are available at http://www.researcherid.com/rid/H-4371-2011.

医動物学


Division of Medical Zoology

Theme of research:

1. Malaria epidemiology and vector control 2. Transgenic mosquito 3. Transgenic malaria parasite 4. Development of malaria vaccine


1. Hiroyuki Matsuoka Professor [email protected] 2. Daisuke Yamamoto Assistant Professor [email protected]


1-1. Malaria epidemiology We have developed simple techniques for malaria diagnosis and G6PD activity test. These can be used in rural areas, where no water and no electricity are available. We are visiting malaria endemic areas in Asian and African countries to demonstrate these methods. 1-2. Vector control in tropical areas To reduce vector mosquitoes in tropical countries, we are testing the efficacy of copper solution. Because copper can give damage to mosquito larvae in very low concentrations. 2. Transgenic mosquitoes To reduce malaria transmit ability of Anopheline mosquitoes, we are adding some genes in Anopheles stephensi (Jichi Med Univ) and A. gambiae (Noguchi Institute, Ghana). 3. Transgenic malaria parasites To observe the movement of malaria parasite (Plasmodium berghei), we have introduced GFP gene or luciferase gene in the parasite. We are now able to follow the movement of malaria parasite in the skin, in the blood and in the mosquito organs. 4. Development of malaria vaccine For malaria vaccine development, we focus on its cytotoxic T lymphocytes: the essential factor for anti-malaria immunity. Through analysis of activated / expanded cytotoxic T lymphocytes by attenuated malaria sporozoite immunization, we try to find the essential malaria antigens for anti-malaria immunity.

臨床感染症学


Division of Clinical Infectious Diseases, Department of Infection and Immunity

Theme of research:

Healthcare-associated Infection Prevention and Control, including Environmental

Bacteriology, Occupational Safety and Health for Healthcare Providers, and

Antimicrobial Stewardship


Yuji Morisawa, MD, Associate Professor, [email protected]


The Division has been established since 2004, to promote patient safety and healthcare

personnel safety. With the Jichi Medical University Hospital and affiliated hospitals in

Tochigi region as research fields, we are focusing on the prevention and control of

healthcare-associated infections. We have reported the Bacillus cereus outbreak

originated from highly contaminated hospital linens, to make nation-wide regulations

anew.

Antimicrobial stewardship is another concern. We would like to innovate an original

program to train infectious diseases specialists fit in real Japan.

分子薬理学部門


Department of Pharmacology, Division of Molecular Pharmacology

Theme of research:

Molecular pharmacology of G-protein coupled hormone receptors as drug targets.


Taka-aki Koshimizu, Associate professor, [email protected]


Our laboratory focuses on the study of G-protein-coupled receptors to develop novel

drug therapy. By using chemical tools specifically designed for this receptor family, we

are trying to understand underling mechanism for a variety of pharmacological responses

occurring in different biological systems, from cells to organs and to whole bodies.

Among the different biological responses caused by a drug treatment, we can now look

into transcriptome, proteome and transcription factor binding sites in a genome-wide

scale, to find a new therapeutic target or marker molecule. Delineating mechanism of drug

side effects is another important topic in our laboratory. Students in our group will learn

how to design and perform pharmacological experiment, analyze own data by integrating

large public database, and publish their work in a scientific journal.

臨床薬理学


Division of Clinical Pharmacology, Department of Pharmacology

Theme of research:

Toxicogenomics


Akio Fujimura, Professor, [email protected]


To clarify the mechanisms of drug toxicity and develop safer agents, effects of various medications on gene expression are analyzed in genome-wide basis using the gene chips. We have found useful biomarkers indicating potential renal toxicity of agents in human.

臨床薬理学


Division of Clinical Pharmacology, Department of Pharmacology

Theme of research:

Chronopharmacology and Chronotherapy


Akio Fujimura, Professor, [email protected]


A number of physiological functions such as central neuron activity, hormone secretion and blood pressure show daily rhythms. In addition, the expressions of many enzymes involved in xenobiotic detoxification (cytochrome P450 enzymes and drug transporters) are also changed during a 24-hour period. Because of these daily rhythms, pharmacokinetics and/or pharmacodynamics of drugs are altered by its dosing-time. Chronopharmacolgy/Chronotherapy is one of the approaches to increase the effects of drugs and to decrease their adverse effects by optimizing the dosing-time.

環境予防医学


Department of Environmental and Preventive Medicine

Theme of research:

Developmental immunotoxicology by endocrine disrupting chemicals


Fujio Kayama, M.D., Ph.D., Professor, [email protected]


Growing fetus and neonates are very vulnerable to the environmental factors. Chemicals such as arsenic, lead and lipid-soluble persistent organic pollutants such as DDT and PCBs are easily transferred into the growing fetus through placenta. Blood-placenta barrier does not function well enough for these man-made chemicals. Endocrine disruptors such as DDT, and PCBs are used as a model chemical to examine the effects on developing immune systems in fetus and neonates of mice and rats. In this projects, we will study adverse effects of chemicals on immune functions and host resistance such as efficacy of vaccination, and antibody production.

環境予防医学


Department of Environmental and Preventive Medicine

Theme of research:

National Birth Cohort Study in chemical exposure


Fujio Kayama, M.D., Ph.D., Professor, [email protected]


Fetus and infants has exposed to many kinds of chemicals in their early life. Specially, it is well-known that a certain chemical has a narrow window to affect fetal development and eventually the outcome will be surfaced in the later days in their juvenile period or adulthood. To answer these difficult questions, we started the National Birth Cohort Study sponsored by Ministry of Environment, Japan. We also started an epidemiological study of pregnant women in Pakistan, who exposed to arsenic (As) by drinking the well water. As a graduate student, you can study the topics and use our existing data set to be analyzed and publish papers as well as helping organizing the projects.

人体病理学


Division of human Pathology, Department of Pathology

Theme of research:

Sex hormones and cell growth.


Akira Tanaka MD,PhD.


Using androgen-dependent mouse mammary SC-3 cells, we have found that androgen-induced expression of FGF8 is essential for the androgen-dependent growth of SC-3 cells. In addition, we have also found that FGF8 is frequently expressed in human prostate and breast cancers. We are now under investigation on the subjects described below:

① Molecular mechanism of the FGF8 gene regulation by androgen.

② Molecular mechanism of acquisition of androgen insensitivity after androgen

withdrawal.

③ Investigation on non-generic signaling pathways stimulated by androgen in SC-3 cells.

統合病理学


Division of Integrative Pathology, Department of Pathology

Theme of research:

Molecular Targeted Therapy of Cancer, Epigenetics, microRNA and Cancer,

Cancer-stromal interaction, Tumor Microenvironment


Toshiro NIKI, Professor;

Daisuke Matsubara, Associate Professor;

Taichiro Yoshimoto, Assistant Professor;


We have been interested in identification of new molecular targets in carcinomas of the

lung and gastrointestinal organs. One line of research ongoing in our lab focuses on

cancer-stromal interaction and microenvironment; both of these topics are currently

investigated using in vitro 3-dimensional culture and xenograft models. Another line of

research focuses on epigenetics and recently described class of small regulatory RNAs

known as microRNAs (miRNAs). Accumulating evidence demonstrates that miRNAs

play key roles in normal physiology and are commonly dysregulated in various human

diseases. We are trying to understand how aberrant miRNA activity contributes to

disease states such as cancer. Epigenetics involves changes in DNA and chromatin

structure, such as genomic imprinting, DNA methylation, and histone modification,

and these epigenetic changes are remembered by the cells when they divide. Projects

are now underway to elucidate the epigenetic alterations that underlie the differences

between cancer and normal cells.

循環器内科学

Department/Division: Division of Cardiovascular Medicine, Department of Medicine

Theme of research: Development of new technologies in blood pressure monitoring, and clinical study projects on morning and nocturnal hypertension.

Name of main researcher, title, and e-mail address: Kazuomi Kario, MD, FACP, FACC, F AHA, FESC, Professor, [email protected]

Brief explanation of research activity: Our department has organized the following ongoing projects for clinical research. 1)Development of new technologies in the blood pressure monitoring

We have developed IT monitoring for management of hypertension. In particular, when the east-Japan earthquake occurred, we set up and utilized this system (the Disaster Cardiovascular Prevention Network [D-CAP]). DCAP is a system which installs a sphygmomanometer with a communication function in a shelter, and transmits the measured blood-pressure value to a computer server. And it is possible to specify higher-risk patients in inputting a DCAP risk score and prevention score into a system. By now, the Great East Japan Earthquake evacuees from Minami Sanriku-cho area have been able to leave the shelter. In order to continue taking measurements, they were given individual blood pressure monitor systems. We would like to analyze these accumulated data and evaluate the cardiovascular risk caused by blood pressure variation. References Kario K, Nishizawa M, Hoshide S, Shimpo M, Ishibashi Y, Kunii O, Shibuya K. Development of a disaster cardiovascular prevention network. Lancet. 2011; 378: 1125-7. Nishizawa M, Hoshide S, Okawara Y, Shimpo M, Matsuo T, Kario K. Aftershock Triggers Augmented Pressor Effects in Survivors: Follow-Up of the Great East Japan Earthquake. Am J Hypertens. 2015 Apr 18. [Epub ahead of print] 2)Japan Morning Surge-Home Blood Pressure (J-HOP) Study

The aim of this study is to investigate the relationship between home BP and target organ damage and cardiovascular outcome to make Japanese hypertension guideline. The patients with one more than cardiovascular risk factor, 4566 subjects, have enrolled and followed up from 74 institutes.

References Kario K, Hoshide S, Haimoto H, Yamagiwa K, Uchiba K, Nagasaka S, Yano Y, Eguchi K, Matsui Y, Shimizu M, Ishikawa J, Ishikawa S; the J-HOP study group. Sleep Blood Pressure Self-Measured at Home as a Novel Determinant of Organ Damage: Japan Morning Surge Home Blood Pressure (J-HOP) Study. J Clin Hypertens (Greenwich). 2015 Feb 16. Hoshide S, Kario K, Yano Y, Haimoto H, Yamagiwa K, Uchiba K, Nagasaka S, Matsui Y, Nakamura A, Fukutomi M, Eguchi K, Ishikawa J; J-HOP Study Group. Association of morning and evening blood pressure at home with asymptomatic organ damage in the J-HOP Study. Am J Hypertens. 2014 Jul;27(7):939-47. 3)Japan Ambulatory Blood Pressure Prospective (JAMP) Study

The Japan Ambulatory Blood Pressure Prospective Study (JAMP study) began in January 2010. The study aims to create an ABPM database from 10,000 high risk subjects with cardiovascular risk in Japan to understand the status of blood pressure control by region and clarify for which the components of 24-hour blood pressure are important for predicting cardiovascular event, JAMP study will clearly answer these questions in clinical practice. 6112 patients have been enrolled from 111 institutes.

References Yano Y, Hoshide S, Tamaki N, Inokuchi T, Nagata M, Yokota N, Hidaka T, Kanemaru Y, Matsuda S, Kuwabara M, Shimada K, Kario K. Regional differences in hypertensive cardiovascular remodeling between fishing and farming communities in Japan. Am J Hypertens. 2011; 24:437-443.

循環器内科学

4)Sleep Pressure and disordered breathing in REsistant Hypertension And Cardiovascular Disease (SPREAD) Registry

We have developed a new device to detect sleep BP level triggered desaturation caused by sleep apnea syndrome. The aim of this study is to study the relationship between frequency of sleep apnea syndrome and nocturnal hypertension in the patients of refractory hypertensive and cardiovascular disease by using the sphygmomanometers to measure the blood pressure surge due to the nighttime hypoxia. In addition, the aim of this study is to identify the high risk patients and provide them the optimal treatment from these results. The plan is to follow up the cases in this registry including of their baseline data to investigate the causal relationship between the frequency of sleep apnea syndrome and pathologies of blood pressure surge. Presently, 893 patients have been enrolled from 25 institutes.

References Shirasaki O1, Kuwabara M, Saito M, Tagami K, Washiya S, Kario K. Development and clinical application of a new technique for detecting 'sleep blood pressure surges' in sleep apnea patients based on a variable desaturation threshold. Hypertens Res. 2011 Aug;34(8):922-8.

腎臓内科学


Division of Nephrology and Kidney Center, Department of Internal Medicine

Theme of research:

① Cardiovascular complications in dialysis patients

② The role of Klotho protein, anti-aging hormone, in CKD patients


Daisuke Nagata, Professor, [email protected] Shigeaki Muto, Professor, [email protected] Osamu Saito, Associate Professor, [email protected] Tetsu Akimoto, Associate Professor, [email protected]


Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease (CVD). Dialysis patients in Japan have already exceeded 29,000 persons, and it is shown that the patients with CKD including dialysis had higher mortality from CVD. The kidney expresses Klotho gene, which may function as an anti-aging hormone. Klotho protein which is a product of the Klotho gene, may decrease with the progression of CKD. Therefore, we hypothesize that the Klotho protein is related to higher occurrence rate of CVD in CKD patients. The role of Klotho gene or protein in the formation of the arteriosclerotic lesion, bone and vascular complications in CKD patients, will be investigated.

消化器内科学


Division of Gastroenterology, Department of medicine

Theme of research:

・ Double-balloon endoscopy (#1)

・ Enodoscopic submucosal dissection for early gastrointestinal neoplasm (#2)

・ Clinical use of Flexible spectral Imaging Color Enhancement（FICE）and Blue Laser

Imaging (BLI) (#3)

Name of main researcher, title, and e-mail address

Hironori Yamamoto (#1.2.3), Professor, [email protected] Hiroyuki Osawa (#3), Associate Professor, [email protected]


・Presentation at medical conferences

・Reporting to medical journals

呼吸器内科学


Division of Pulmonary Medicine, Department of Medicine

Theme of research:

Impaired Toll-like Receptor-Mediated Inflammatory Response in the Alveolar Macrophages of Streptozotocin-Induced Diabetic Mice


Hideaki Yamasawa, MD, [email protected]


Toll-like receptors (TLRs), that recognize conserved pathogen-associated molecular patterns, play a role in the recognition of invading pathogens and initiate inflammatory responses, including the production of proinflammatory cytokines. Diabetes mellitus is often identified as an independent risk factor for the development of lower respiratory tract infections. Alveolar macrophages (AM) constitute the first-line defense against inhaled pathogens. We therefore investigated the effect of hyperglycemia on TLR-mediated proinflammatory cytokine production by AM. Experimental hyperglycemia was induced in Balb/c mice by the intraperitoneal injection of streptozotocin. We have demonstrated that hyperglycemia impaired the responsiveness of the alveolar macrophages to multiple TLR agonists by inhibiting the production of proinflammatory cytokines. Our present interest is the mechanisms of these inhibitory effects. Therefore we are conducting the further investigations focusing on the hyperglycemia-induced alterations in intracellular signaling.

神経内科


Division of Neurology, Department of Medicine

Theme of research:

Gene therapy for neurodegenerative diseases


Shin-ichi Muramatsu, Professor


Our research aims to develop novel therapies for major neurodegenerative diseases

such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS).

Gene therapy: After our successful preclinical research for a primate PD model via

stereotactic injection of AAV vectors expressing dopamine (DA)-synthesizing

enzymes: tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC),

and GTP cyclohydrolase I, we are now conducting a clinical research of gene thrapy

for advanced cases of PD with a stereotactic intraputaminal injection of AAV-AADC

combined with oral L-DOPA administration. In transgenic ALS mice, our research of

intramuscular AAV-GDNF transfer exhibited protective effects on spinal motoneurons.

These methods using AAV vectors may offer novel and feasible treatment options in

neurodegenerative disease.

Cell therapy: Another interest of our research is regenerative medicine using primate

embryonic stem (ES) cells. By cultivating in astrocyte-conditioned medium, we

induced neural stem cells from primate ES cells, and have shown restoration of DA

function in a primate model of PD after transplantation of the neural stem cells.

血液学


Division of Hematology, Department of Medicine

Theme of research:

1) Molecular analysis of c-Cbl. 2) Analysis of anti-GVHD effects of MSCs. 3) Analysis of tumor supporting effects of MSCs


Takahiro Suzuki Assistant Professor [email protected] Kazuya Sato Assistant Professor [email protected] Iekuni Oh Assistant Professor [email protected]


1) Recently, we and our collaborators found novel point mutations in a proto-oncogene, c-cbl, in some samples derived from MDS patients. With the gene mutations, mammalian cells can be transformed into tumor cells. We are investigating the molecular mechanisms of transformation induced by these gene mutations. We are also investigating the functions of c-Cbl for cytoskeletal regulation using c-Cbl knockout mice. 2) 3) It has been reported that MSCs (Mesenchymal stromal cells) may potentially attenuate GVHD after bone marrow transplantation. But molecular mechanisms of immunomodulation by MSCs are still obscure. We are investigating the mechanisms of MSC-mediated suppression of immune response by using in vivo murine transplantation models. It is also known that MSCs can support hematopoietic malignant cells. We also investigate tumor supporting effects of MSCs. Publications 1) Suzuki T, Oh I, Ohmine K, Meguro A, Mori M, Fujiwara SI, Yamamoto C, Nagai T, Ozawa K. Distribution of serum erythropoietin levels in Japanese patients with myelodysplastic syndromes. Int J Hematol. 2015 Jan;101(1):32-6. 2) Okabe H, Suzuki T, Uehara E, Ueda M, Nagai T, Ozawa K., The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice. Eur J Haematol. 2014 Aug;93(2):118-28.

血液学


Division of Hematology, Department of Medicine

Theme of research: 1) Development of novel adaptive immune gene therapy for hematological malignancy

Name of main researcher, title, and e-mail address: Ken Ohmine; Assistant Professor [email protected] Iekuni Oh; Assistant Professor [email protected] Kiyoshi Okazuka Clinical Associate [email protected]

Brief explanation of research activity: Adoptive immunotherapy with CD19-specific chimeric antigen receptor (CAR) gene transduced T cells has been shown to be very promising for refractory hematologic malignancies. We are conducting a phase 1/2 clinical trial to evaluate the safety and efficacy of CD19-CAR-T in patients with relapsed or refractory non-Hodgkin lymphomas. Patient’s autologous T cells were transduced with a retrovirus encoding a CAR construct composed of anti-CD19 scFV linked to CD28 and CD3ζ;signaling domain and expanded with RetroNectin/OKT3 stimulation. Patients are administered cyclophosphamide as a lymphodepletion ending two days before CAR-T infusion and receive either 1 x106 cells/kg (dose level 1), 3 x106 cells/kg (dose level 2), or 1 x107 cells/kg (dose level 3) of CAR-T. Enrollment started in December 2014. (Clinicaltrials.gov, identifier; NCT02134262). Publications 1) Uchibori R, Tsukahara T, Ohmine K, Ozawa K. Cancer gene therapy using mesenchymal

stem cells. Int J Hematol. 99(4):377-82, 2014. 2) Ishihara A, Ohmine K, Weisbrode SE, Bertone AL. Effect of Intra-Medullar and

Intra-Venous Infusions of Mesenchymal Stem Cells on Cell Engraftment by In-Vivo Cell Tracking and Osteoinductivity in Rabbit Long Bones: A Pilot Study. Orthop Muscular Syst.3(3), 2014.

3) Tsukahara T, Iwase N, Kawakami K, Iwasaki M, Yamamoto C, Ohmine K, Uchibori R,

Teruya T, Ido H, Saga Y, Urabe M, Mizukami H, Kume A, Nakamura M, Brentjens R, Ozawa K. The Tol2 transposon system mediates the genetic engineering of T-cells with CD19-specific chimeric antigen receptors for B-cell malignancies. Gene Ther. 22(2):209-15, 2015

内分泌代謝学


Division of Endocrinology and Metabolism, Department of Medicine

Theme of research:

Neutral lipid metabolism and cardiometabolic diseases


Shun Ishibashi, Professor, [email protected]


Obesity, diabetes and atherosclerosis are the leading causes of morbidity and mortality in industrialized countries including Japan. These cardiometabolic diseases are characterized by excessive accumulation of neutral lipids in various organs. For example, triglycertides and cholesterol esters are accumulated in adipose tissues and vascular walls, respectively. Therefore, elucidation of the mechanisms underlying the synthesis and hydrolysis of these neutral lipids is important to understand the pathophysiology of the cardiometabolic diseases and to develop new treatment for them. Previously, we generated mice lacking acyl-CoA:cholesterol acyltransferase (ACAT) or hormone-sensitive lipase (HSL). Phenotypic analyses of these mice led us to find new functions of these enzymes. By bioinformatic approach, furthermore, we identified new members of neutral lipid esterase family which are involved in adipocyte lipolysis(CES1) and cholesterol ester hydrolysis in macrophages(NCEH1). One of them, for example, is substantially expressed in adipose tissues and its expression is significantly correlated with adiposity in humans. We are now trying to determine relative contribution these multiple enzymes to the neutral lipid hydrolysis in adipocytes and macrophages. We are also examining whether inhibitors of the neutral lipids inhibit the development of the cardiometabolic diseases using animal models.

内分泌代謝学



Theme of research:

Transgenic dissection of cholesterol biosynthetic pathway




Cholesterol biosynthetic pathway provides not only cholesterol (sterol pathway) but also other derivatives with significant biological activities like isoprenoids, dolichol and ubiquinone (non-sterol pathway). HMG-CoA reductase (HMGCR) is the rate limiting step for both sterol and non-sterol pathway, while squalene synthase (SS) is the first committed enzyme for sterol pathway. In order to define the role of these in enzymes in the cholesterol homeostasis, we generated mice lacking HMGCR or SS in the liver or macrophages using Cre/loxP technology. HMGCR is essential for survival and SS is dispensable for cholesterol biosynthesis. We hope there results will help us develop better pharmaceutical drugs than statins, which are widely used in the current clinical setting, to treat lipid disorders and atherothrombotic diseases.

内分泌代謝学



Theme of research:

Genetic analysis of metabolic diseases.




Significant proportion of plasma lipid levels is genetically determined. We are performing genetic analyses of patients with these disorders, particularly focusing on hyperchylomicrinemia syndrome and severe insulin resistance syndrome. In addition to deficiency of lipoprotein lipase and apolipoprotein CII insulin receptor, apo AV and other novel genes have emerged as the causative genes.

アレルギー膠原病学


Division of Rheumatology and Clinical Immunology

Theme of research:

1) New Treatment of Rheumatoid Arthritis

2) Mechanism of RA Development in Human

3) Clinical Importance of MMT-3 in RA

4) Importance of Anti-CCP antibody in RA


1) Seiji Minota, Professor, MD, PhD: [email protected]

2) Masahiro Iwamoto, Associate Professor, MD, PhD: [email protected]

3) Takao Nagashima, Associate Professor, MD, PhD: [email protected]

4) Katsuya Nagatani, Associate Professor, MD, PhD: [email protected]


1) Examining the effects of various drugs or supplements on the prevention of RA development

induced by immunization of collagen type II in mice. Also examining these drugs and materials on

the disease-abating effects after RA development.

2) Examining which gene(s) is expressed first during the development of human RA and pursuing the

possibility of the gene(s) to detect earliest relapse.

3) Examining clinical importance of the serum level of metalloproteinase 3 in RA patients and the

influence its serum levels under glucocorticoid-use.

4) Making human monoclonal anti-CCP antibody using lymphocytes from RA patients with a high

titer of it and pursuing the clinical significance of RA development in human.

皮膚科学


Department of Dermatology

Theme of research:

The roles of epidermal keratinocytes in inflammatory skin diseases


Mayumi Komine, M.D., Ph.D., Associate Professor


1) Epidermis is the outermost tissue protecting human body from environmental stresses, and responds to various kinds of environmental stimuli. We focus on the role of epidermal keratinocytes responding to these environmental stimuli, such as mechanical stress, ultraviolet light, microbes, and wounding.

2) Psoriasis is one of the inflammatory skin diseases, and various novel therapeutics have been developed, however, the curative treatment have not been established. We have outpatient psoriasis clinic, and try several clinical studies on psoriasis.

3) Many cutaneous diseases are inherited, and we try to identify the causative mutations in patients of hereditary skin disorders, such as epidermolysis bullosa, epidermolytic ichthyosis, palmoplantar keratoderma, and steatocystoma multiplex.

4) We have many patients with autoimmune bullous diseases. We are investigating the signaling pathways provoked by antibody binding to epidermal keratinocytes, and the following production of inflammatory cytokines.

5) Epidermal keratinocytes and vascular endothelial cells produce interleukin-33, which works as an “alarmin”. We investigate the mechanism of production and the role of IL-33 in inflammatory skin diseases and wound healing processes utilizing IL-33 knockout mice, and mice models of inflammatory skin diseases.

放射線医学


Department of Radiology, Division of diagnostic and interventional radiology

Theme of research:

Cardiac radiology: Assessment the accuracy of dual source computed tomography (DSCT) to detect cardiac coronary disease and left ventricular wall motion abnormalities. Gastrointestinal radiology: Colorectal cancer screening using CT colonography (CTC). Body MR imaging: MR imaging for cancer detection and characterization using non-contrast technique. Musculoskeletal radiology: The evaluation of bone erosions in Rheumatoid Arthritis with CT and MRI.Neuroradiology: Unilateral amygdala enlargement with temporal lobe epilepsy Head and Neck radiology: Multimodality imaging such as CT, MRI, and PET-CT of the head and neck cancer. Nuclear medicine: Impact of whole-body 18FDG-PET/CT on diagnosis of pulmonary mass lesions and therapeutic management of lung cancer. Pediatric radiology: Evaluation of radiation dose in pediatric CT and fluoroscopy Interventional radiology: Efficacy of percutaneous trans-hepatic angioplasty with use of intravascular ultrasound for portal venous complication after pediatric living donor liver transplantation.


Yuko Otake, MD., Clinical assistant professor, [email protected] Shigeyoshi Kijime, MD., Clinical assistant professor, [email protected] Yukio Kimura, MD., Clinical assistant professor, [email protected] Takeshi Shinozaki, MD., Assistant professor, [email protected] Akifumi Fujita, MD., Assistant professor, [email protected] Rieko Furukawa, MD., Senior resident, [email protected] Waka Nakata, MD., Clinical assistant professor, [email protected] Shigeru Kobayashi, MD., Clinical assistant professor, [email protected] Hideharu Sugimoto, MD., Professor and Chairman, [email protected]


Clinical research has been an important part of the Department of Radiology, Jichi Medical University since the Dr. Sugimoto, professor and chairman had succeeded to the former chair. At present, the faculty members of the department are engaging in various fields of diagnostic and interventional radiology, even though the workload of the department is significantly increasing in the past 10 years. In 2012, two 3.0 T MRI were installed. Now, we have 5 MR units, 4 high-end CT scanners, PET-CT and SPECT-CT, and advanced angiographic units. Using this equipment, faculty members and fellows are performing clinical researches. A part of the activity is listed in the theme of research. Further, we had clinical MRI, CT, and DSA in the laboratory for the large animals, such as piglet.

精神医学


Psychiatry

Theme of research:

1. The effect of 3,4-methylenedioxymethamphetamine ('Ecstasy') on monoamine metabolism in the rat anterior hypotalamus: the role of dopamine and serotonin.

2. Effect of chronic interferon-alpha on extracellular dopamine and serotonin concentrations in the rat prefrontal cortex.

3. Time series analysis of human electrocorticogram from subdural electrodes during wakefulness and sleep.

4. NK cell activity and blood pressure in patients with mood disorder. 5. Evaluation of cerebral activity after social skill’s training to schizophrenic patients

by using fMRI and NIRS. 6. Study on the long-term courses of mood disorders. 7. Duration of untreated psychosis and 1 to 2-year outcome of first contact psychoses.8. Effectiveness of multidisciplinary treatment system on eating disorder. 9. Transcultural psychiatric studies on the relationship of acculturation process to

mental health among Japanese Latin Americans in Japan. 10. Mental disorders and creativity.

Name of main researcher, title, and e-mail address: Professor Takaaki Abe Professor Otsuka Koichiro

Assistant professor Toshiyuki Kobayashi e-mail : [email protected] Lecturer Senichiro Kikuchi Lecturer Katsutoshi Shioda Lecturer Shiro Suda Lecturer Masaki Nishida

Brief explanation of research activity: We continue to develop various researches in the field of

1) biological psychiatry such as psychopharmacology, psychophysiology as well as 2) psychopathology such as social psychiatry, transcultural psychiatry, art therapies,

pathography(creativity), trying to bridge two approaches based on clinical experience.

小児科学


Department of Pediatrics

Theme of research:

Molecular studies of autism spectrum disorders; phenotype analyses, genetic variation analyses and identification of sensitive genes.


Takanori Yamagata (Professor [email protected]), Hitoshi Osaka (Professor), Eriko Jimbo (Associate Professor), Naomi Nakashima (Assistant Professor)


Autism spectrum disorder (ASD) is a developmental disorder characterized by the affected social interaction including verbal development and stereotypic behavior. To reveal molecular pathology of ASD, we have been working on the following projects. (1) Candidate gene analyses for the disease-sensitive mutations

Both functional and positional candidate genes have been analyzed for their disease-sensitive mutations on the patients with and without familial predisposition.

(2) Genomic microarray studies, comparative genomic hybridization (CGH) and copy number variation (CNV), are also in progress.

(3) Phenotype – genotype interaction Phenotype – genotype interaction is analyzed with association of Project (1).

(4) Animal model research By using knockout mice for secretin receptor, Gpcrs and other genes in which disease –sensitive mutation was detected in Project (1), several projects are in progress including behavior analysis, neuropathology and molecular studies.

小児科学



Theme of research:

Chromosomal genomic hybridization (CGH) and candidate gene analysis for the patients with multiple anomaly


Takanori Yamagata (Professor), Hitoshi Osaka (Professor), Yasuyuki Nozaki (Assistant Professor)


Chromosomal micro-rearrangements such as micro-deletion or duplication have been reported to be the cause of many diseases including mental retardation and multiple anomaly syndromes. To detect the responsible genes for developmental disorders and/or multiple anomalies including cardiac anomaly, we are analyzing the patients for micro- rearrangement by chromosomal genomic hybridization (CGH) method. And also we analyze the candidate genes for mutations by direct sequencing.

小児科学



Theme of research:

Elucidation of pathogenesis of Langerhans cell histiocytosis (LCH) by osteoimmunological aproach


Akira Morimoto (Associate Professor, [email protected] )


LCH is characterized by a proliferation of CD1a-positive LCH cells intervening with activated T cells, macrophages, eosinophils and osteoclast like multinucleate giant cells, and associated with the lesional ‘cytokine storm’. In the LCH lesions, it has been shown that proinflammatory cytokines, chemokines and other proteins such as RANK-RANKL, OPG play a role. Clinical features of LCH are quite variable from an osteolytic lesion with single system to a fatal disease with multisystem involvements. To date, however, either mechanism of LCH cells proliferation or role of these lesional ‘cytokine storm’ remains unknown We investigate the pathogenesis of LCH by using osteoimmunological approach.

小児科学



Theme of research:

Continuous Infusion of Cyclosporin A (CICyA) treatment for intravenous immunoglobulin resistant Kawasaki disease (KD)


Takaomi Minami (Assistant professor), Tomoyuki Sato (Assistant professor), Takanori Yamagata (Professor)


Intravenous immunoglobulin (IVIG) resistant KD patients had an increased risk of developing coronary artery lesion compared with those with good response. Treatment of intravenous immunoglobulin resistant KD is challenging. We employed CICyA in IVIG-resistant KD patients. The aim of our research is to disclose

1) effect of CICyA 2) side effect of CICyA and 3) mechanism of CICyA in patients with IVIG-resistant KD

小児科学



Theme of research:

Treatment of genetic neurological disorders in childhood


Hitoshi Osaka (Professor), Takanori Yamagata (Professor)


Our understanding for molecular basis for genetic neuronal diseases is expanding.

However, our goal is not to diagnose but to treat children. Two main topics are focused.

1) Gene therapy: We aim to deliver adeno-associated viral (AAV) vectors, cloned

causative gene, to the central nervous system. Large portion of genetic disorders in

childhood are caused by the functional loss of mutated gene, thus becoming good

candidates for AAV gene therapy. AAV vector is safe and expresses cloned gene

lifelong without carcinogenesis, which makes itself as one of the most promising viral

vectors.

2) iPS cells: Patients derived iPS cell are now available. We are differentiating iPS cells

into cells with neuronal lineage. Disease phenotype appeared in iPS cells or

differentiated cells will be a good target for drug screening. The iPS cells are also useful

resources to evaluate the efficiency of viral gene delivery by AAV and to monitor the

toxicity of drugs before clinical trials.

We challenge, as one team, to find a novel treatment for devastating childhood

neurological diseases.

小児科学



Theme of research:

Developing a new ultrasonic method for evaluating tissue characterization: For

diagnosing of non-alcoholic steatohepatitis


Hideki Kumagai (Associate Professor), Koji Yokoyama (Assistant Professor)


It is important to evaluate the condition of the liver for treatment decision-making

or prognostication. There has been a need to develop non-invasive, repeatable, and

accurate techniques for quantitative evaluation of tissue characteristics in the liver.

Diagnostic techniques that evaluate frequency attenuation or elasticity have been

developed in clinical setting, but evaluation based on sound speed or other image

parameter has not yet been applied clinically. Our ultimate goal is to develop a

non-invasive diagnostic technique capable of tissue characterization by measuring

the speed of sound or other new parameter in the liver.

小児科学

Division/Department: Department of Pediatrics

Theme of research: Mechanistic study on the pathogenesis of idiopathic steroid-sensitive nephrotic syndrome in children Name of main researcher, title, and e-mail address: Takahiro Kanai, MD, PhD (assistant professor), Jun Odaka MD (assistant professor), Takane Ito MD (assistant professor), Takashi Saito MD (assistant professor), and Jun Aoyagi MD (assistant professor) Brief explanation of research activity: Idiopathic steroid-sensitive nephrotic syndrome (ISSNS) is one of the most common chronic renal disease. It’s characterized by edema, massive proteinuria, hypoalbuminemia and hyper cholesterolemia. We have already revealed that CD4+ T cells play important roles in the pathogenesis of this disease [1-9]. On the other hand, there is still a lack of understanding on how CD4+ T cell could develop ISSNS. We’re currently exploring the mechanisms by elucidating the relationship between human CD4+ T cells and hyperlipidemia with biochemical technology (FACS, proteomics), biogenetic technology (cDNA microarray, QT-PCR, ChIP-seq, siRNA) and pathological technology (immune staining) using human samples. 1. Kanai T, Yamagata T, and Momoi MY. Macrophage inflammatory protein-1β and

interleukin-8 associated with idiopathic steroid-sensitive nephrotic syndrome. Pediatr Int. 51: 443-7: 2009.

2. Kanai T, Yotsumoto S, and Momoi MY. Norovirus-associated Renal Acute Renal Failure with Nephrotic Syndrome. Pediatr Int. 52:e23-5: 2010.

3. Kanai T, Shiraishi H, Ito T, Odaka J, Saito T, Aoyagi J, Ueda Y, and Momoi MY. Plasma exchange and tacrolimus therapy for focal segmental glomerulosclerosis collapsing variant and the cytokine dynamics. Ther Apher Dial. 14; 603-605: 2010.

4. Kanai T, Shiraishi H, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J, and Momoi MY. Th2 cells predominate of idiopathic steroid-sensitive nephrotic syndrome. Clin Exp Nephrol. 14: 578-583: 2010.

5. Kanai T, Shiraishi H, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J, and Momoi MY. Elevated serum interleukin-7 level on idiopathic steroid-sensitive nephritic syndrome. Pediatr Int. 53: 906-9: 2011.

6. Odaka J, Kanai T, Ito T, Saito T, Aoyagi J, Momoi MY. Dense deposit disease with steroid pulse therapy. Jichi Medical University Journal. 34: 97-102: 2012.

7. Jun Aoyagi, Takahiro Kanai, Takane Ito, Jun Odaka, Takashi Saito, Mariko Y. Momoi. cytokine dynamics in a 14-year-old girl with tubulointerstitial nephritis and uveitis syndrome CEN Case Reports DOI:10.1007/s13730-013-0084-z

8. Kanai T, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J et al. Apolipoprotein AII levels are associated with the UP/UCr levels in idiopathic steroid-sensitive nephrotic syndrome. Clinical and experimental nephrology. 2014.

消化器・一般外科学


Division of Gastroenterological and General Surgery, Department of Surgery

Theme of research:

Subdivision of Hepato-Biliary Surgery


Hideki,Sasanuma, Atsushi Shimizu, Yoshikazu Yasuda, Yasunaru Sakuma, Masanobu Hyodo, Takehito Fujiwara, Yuji Kaneda, Atsushi Miki, Kazue Morishima, Naoya Kasahara, Masanobu Taguchi, Yukihiro Sanada, Kazuhiro Endo


1. The relationship of the blood flow and pressure among the portal vein, the inferior vena cava and the hepatic artery. An experimental study on pigs.

2. Immunohistochemical study of characteristics of bile duct dysplasia evaluated on the basis of expression of metastasis/invasion-related factors and p53.

3. Swine model for training of living-related liver transplantation. 4. Hepatic arterial infusion chemotherapy for non-resectable colorectal liver metastasis. 5. Influence of simultaneous hepatic resection on left-sides colonic anastomosis. 6. The analysis of intra luminal blood flow of the portal vein by color-Doppler ultrasound. 7. Gene expression of drug induces hepatitis. 8. Liver regeneration 9. Islet transplantation

10. 肝再生

11. Islet & Liver transplantation



Surgery, pathology1, physiology2

Theme of research:

1. Basic research of esophageal cancer 2. Ghrelin and gastric surgery


Main researcher ：Yoshikazu Yasuda

1.Shin Saito, Takashi Ui 2.Masaru Koizumi, Masanobu Taguchi


1. Saito S, et al: A clinicopathological study of basaloid squamous carcinoma of the esophagus. Esophagus 6:177-181, 2009

2. Koizumi M, et al. Reconstruction-dependent recovery from anorexia and time-related recovery of regulatory ghrelin system in gastrectomized rats. Int J Pept. 2010

3. Koizumi M, et al Postoperative weight loss does not resolve after esophagectomy despite normal serum ghrelin levels. Ann Thorac Surg. 2011;91:1032-7.




Theme of research:

Immunohistochemical analysis of REG I expression in ulcerative colitis-associated

neoplastic lesions


Hiroyuki Tanaka, Yoshikazu Yasuda,


Background and aims: The regenerating gene (REG) Ihas been identified by microarray analysis as a gene that is distinctly overexpressed in ulcerative colitis, and its protein product is suggested to play a pivotal role in the development of UC-associated carcinoma. In the present study, we investigated the significance of REG I expression as a diagnostic marker of UC-associated neoplasia. Methods: Tissue samples were obtained from colectomy specimens from 31 patients with long-standing UC (mean disease duration 17.2 years, range 5-29 years). The lesions were evaluated according to the International Classification for Dysplasia in Inflammatory Bowel Diseases, and the sections were examined using immunohistochemistry for REG I and P53. Results: In the ‘regenerating atypia’ group, REG I immunoreactivity was restricted to the lower third of the UC mucosa (Grade 1). Lesions classified as ‘indefinite for dysplasia’ also showed predominantly basal-type staining for REG I. However, in ‘low-grade dysplasia’ and ‘high-grade dysplasia’ lesions, the localization of REG I immunoreactivity expanded to the middle (Grade 2) and upper (Grade 3) third of the UC mucosa, respectively. The REG I immunostaining pattern differed significantly (P <0.0001) between non-neoplastic and neoplastic lesions, and was significantly (P <0.0001) associated with p53 overexpression. Conclusions: Immunohistochemical analysis of REG I expression is useful for differential diagnosis of non-neoplastic and neoplastic lesions in UC tissues.




Theme of research:

Real and virtual 3D modeling of hepato-biliary-pancreatic disease


Naohiro Sata MD, PhD [email protected] Hideki Sasanuma MD PhD [email protected] Masaru Koizumi MD, PhD [email protected] Kazuhiro Endo MD [email protected]


3D modeling is a quite attractive solution for the safe surgical procedure. The aim of this research is evaluation of feasibility of real and virtual 3D model from individual image. From the dataset of MD-CT, individual volume-rendering virtual 3D image is created in the workstation. 3D printer can produce real 3D model of the individual image by post-processing of the dataset. The attendant surgeons would make preoperative simulation of dissection with tactile sense using virtual 3D model. Real 3D model would offer many novel possibilities in the surgical management, intraoperative navigation surgery, education for young doctors, residents, and medical students, tools for informed consent, and so on. This research would provide new aspect of diagnosis and management in hepato-biliary-pancreatic disease.



Department of Surgery

Theme of research:

Liver functional and regenerational analysis of NAFLD with hepatectomy


Atsushi Miki M.D., Ph.D. [email protected]


Non-alcoholic fatty liver disease (NAFLD) or Non-alcoholic steatohepatitis (NASH) is a cause of liver cirrhosis and hepatocellular carcinoma. And epidemiologically the number is growing up gradually according to the change of life style in japan. In part due to improved perioperative care, liver resection has become a standard therapy. However, the surgical outcome in patients with liver cirrhosis remains a problem due to the higher mortality and morbidity rate compared to operations on other organs. There are few reports about surgical outcome of NAFLD or NASH patients. We attempt to analyze the effect of steatohepatitis with surgical outcome and liver regeneration with molecular biological approach using rodents.




Theme of research:

Preoperative estimation of liver functional reserve toward better outcome of hepatectomy


Atsushi Miki M.D., Ph.D., Yasunaru Sakuma M.D.,Ph.D., Yoshikazu Yasuda M.D.,Ph.D


The preoperative estimation of liver function is important to avoid post-hepatectomy liver failure for hepatocellular carcinoma with hepatitis. However, it has been difficult to estimate remnant liver functional reserve due to the variability of regional liver function and lack of system analyzing regional liver function. Recently 99-Tc galactosyl asialoglycoprotein receptor (GSA) scintigraphy reported to calculate the regional liver function better than old style methods. Moreover recently new GSA SPECT/CT machine is introduced in this institute, which could construct 3D image. We try to estimate the regional liver function with GSA scintigraphy by the surgical simulation on the computed software with the fusion image of the GSA scintigraphy SPECT and computed tomography.




Theme of research:

Islet beta cell mass analysis with in-vivo imaging system


Atsushi Miki M.D., Ph.D. [email protected]


Islet cell transplantation is a promising therapy for brittle type I diabetes. Isolated islets are transplanted into liver via portal vain. After transplantation, it could be difficult to assess the number, viability, and function in vivo. We generated a novel reporter system using secreted Gaussia princeps luciferase (GLuc) under the control of a Pdx1 promoter, which was used as a transgene for the generation of reporter mice to monitor Pdx1 promoter activity in vivo via the measurement of secreted GLuc activity in a small aliquot of blood. We are working to assess the islet beta cell mass and function in vivo.

心臓血管外科学


Division of Cardiovascular Surgery, Department of Surgery

Theme of research:

Left ventricular remodeling after surgical treatment


Professor Yoshio Misawa, [email protected]


Left ventricular remodeling after surgical treatment in patients with left ventricular volume overloading diseases such as aortic valve regurgitation or mitral valve regurgitation is serially followed by UCG study. Optimal timing for these diseases is discussed.



Division of Cardiovascular Surgery, Department of Surgery

Theme of research:

Cardiovascular surgery to elderly people


Shin-ichi Oki


The risk of an operation also increases with a cardiovascular patient's aging. Although the fall of clear operation results now is not accepted by careful selection of surgical indication as compared with a youth, expansion of surgical indication is needed with increase of the number of elderly-people patients. The feature of a cardiovascular operation of elderly people is grasped, and investigation of surgical indication is performed.



Division of CV Surgery, Department of Surgery

Theme of research:

1. Development of left ventricular assist device

2. Biocompatibility, antithrombogenicity, and physiology of rotary blood pump

3. Clinical research of acute aortic dissection


Koji Kawahito, professor, [email protected]


1. Development of left ventricular assist device. We have developed axial flow ventricular assist

device (VAD) in corporation with NASA/Johnson Space Center in Houston. This device named

Micromed/DeBakey VAD (formerly knowed as NASA/DeBakey VAD) is now used for permanent

ventricular assist in US and Europe.

2. We have been studying biocompatibility, antithrombogenicity, and physiology of rotary blood pump

from viewpoints of neutrophil activity, platelet activity, and proinflammatory cytokines.

3. We have been studying short term and long term surgical results of acute aortic dissection. The

focus of these studies are preoperative risk analysis, mechanism of malperfusion, and newly

developed surgical techniques.

呼吸器外科学


Division of General Thoracic Surgery, Department of Surgery

Theme of research:

Vital observation of small pulmonary vessels in the rat with a soft X-ray system.


Shunsuke Endo, Professor and Chairman Kenji TETSUKA, M.D., Assistant Professor


Vasoconstriction and vasodilatation of small pulmonary vessels (200~500μ) are very important in regulation of pulmonary circulation. We developed a vital observation technique for small pulmonary vessels in the rat lung by soft x-ray system. Now, we are studying the mechanisms of hypoxic vasoconstriction by using this system.

呼吸器外科学



Theme of research:

Drug delivery system via liquid ventilation


Shunsuke Endo, M.D.PhD. Professor and Chairman


Alveolar recruitment can be completed using liquid ventilation after acute lung injury where drug can not be sufficiently delivered due to derrangement of pulmonary microcirculation. Efficacy of drug delivery system using liquid ventilation is evaluated by visualization through a vital fluorescent microscopy.

呼吸器外科学



Theme of research:

Control of polymorphonuclear leukocyte- endothelial interaction during surgical stress.


Shinichi Otani, Assistant Professor


During surgical stress, improper activation of PMN may contribute to local or global tissue injury such as acute respiratory syndrome and multiple organ failure syndrome. polymorphonuclear leukocyte-endothelial interactions play a central role in the pathogenic process and could be a target for therapies to prevent or treat such injuries. The aim of this research is to control polymorphonuclear leukocyte-endothelial interaction during surgical stress. We developed a novel model of green fluorescent protein transgenic rat for real time observation of PMN transit in pulmonary microcirculation.

小児外科学


Pediatric Surgery

Theme of research:

Pediatric Surgery


Shigeru Ono, Professor: [email protected]


1) Study of cancer stem cell in children

2) New treatment strategy for tracheal stenosis

3) Development of new surgical technology in Pediatric Surgery

移植外科学


Division of Transplant Surgery，Department of Surgery

Theme of research:

1) Innovation of new organ preservation solution. 2) Selection of proper immunosuppressive agents by lymphoblast genesis. 3) Development of hepatic artery anastomosis by using microsurgical technique


1) Hideo Kawarasaki (Professor) [email protected] 2) Koichi Mizuta(Associate Professor) [email protected]


One hundred fifty two pediatric liver transplantation from live donor has been performed at our institution since May, 2001. Our research work is strongly related to our daily clinical activities. 1)University of Wisconsin(UW) solution is world wide available as an organ preservation solution. As this solution is extra cellular type, this needs to be washed out just before hepatic blood circulation. Intra cellular type preservation solution which needs not to be irrigated has been innovated by us. 2)It will be possible to select proper immunosuppressive agent by this new method, lymphoblast genesis. 3)As a size of the hepatic artery is small in children, hepatic artery stenosis and thrombosis are often reported in pediatric liver transplantation. Microsurgical technique enables us to perform safe anastomosis of the hepatic artery.

形成外科学


Department of Plastic Surgery

Theme of research:

Keloid biology


Ataru Sunaga, M.D. [email protected]


We have just started a new project funded by a Grant-in-Aid for challenging Exploratory Research by the Japanese Ministry of Education, Culture, Sports, Science, and Technology. The long term research goal of our lab is to understand the pathogenesis and the pathophysiology of keloids.

脳神経外科


Department of Neurosurgery

Theme of research:

Biological and electrophysiological study using congenital epileptic EL mice


Keiji Oguro, Hidenori Yokota, Eiju Watanabe


EL mouse is an epileptic model animal which develops temporal lobe epilepsy-like

attacks after 10W from birth. Our experimental purpose is to reveal the mechanisms

underlying temporal lobe epilepsy. By electrophysiological methods using hippocampal

slice of EL mice, we found out abnormal hyper-excitability in CA3 region which might

explain the mechanisms of temporal lobe epilepsy. Now we are trying to find further

molecular mechanisms which induce the hyper-excitability and to develop a new

therapeutic method for clinical field.

脳神経外科



Theme of research:

Functional Brain Mapping Using Optical Topography for the Parkinson’s Disease patients with Deep Brain Stimulation Therapy


Takeshi Nakajima, Eiju Watanabe


Introduction

Optical Topography (OT) can monitor the brain tissue oxygenation and its kinetics. Using OT, we have studied the hemodynamic

change of the brain and the regional activation as correspond to the cerebral blood volume (rCBV). Positron emission

tomography (PET) and single photon emission CT (SPECT) studies were previously reported that deep brain stimulation (DBS)

therapy for the Parkinson’s disease patients, made rCBV change clinically. Former methods could detect only the steady state of

the hemodynamic conditions; we could measure the change of the rCBV continuously by the OT.

Methods

The subjects were nine Parkinson’s disease patients treated DBS therapy for the bilateral subthalamic nucleus. The rCBV were

measured by 44-channel OT with both movement and recognition tasks. For the movement task, we employed the repeated

hand-grasping movement, and for the recognition task, did intentionally losing on the

Rock-Paper-Scissors. The Rock-Paper-Scissors, the way to win or lose, is a common game in Japan, like tossup in the world. The

rule is that rock win scissors, scissors win paper, but paper win rock. Then, people tend to win unconsciously despite of being

asked to lose. Losing Rock-Paper-Scissors need recognition and conflict, therefore we use this as recognition task as “no-go

reaction”. Study protocol was that patients were measured rCBV during movement task and recognition task with DBS off first,

then, they practiced the same tasks with DBS on and were examined again. All of these protocols were not easy to implement and

could be performed in about 30 to 40 minutes.

Results

Five patients were studied with motor tasks, and nine were with recognition tasks. About the motor functions, two of five patients

showed increase of rCBV at dominant frontal cortex or motor area by DBS on grasping task. In the other two patients of rest

three, rCBV of the interest area was decreased. In the recognition tasks study, rCBV of the normal volunteers tended to increase

at the lateral pre-frontal cortex of dominant side to the Losing Rock-Paper-Scissors tasks. Among the DBS patients, four of nine

were the same pattern as normal volunteers, but the other three responded opposite way, decreased rCBV were observed in the

corresponded cortex.

Discussion

In the patients whose rCBV were increased with DBS on, it seems that DBS made their CBV pattern normally and that lead

improving of their movement. On the other hand, patients that DBS could not make increase rCBV were thought that they had

already made increase their CBV during these tasks without DBS. Then, it is possible that DBS make their effort easier and they

did not need to make CBV increase. We could interpret that this could be an effect of STN-DBS, modification of rCBV for

normalizing pattern. The OT examination may be a useful tool for evaluation of the effect of STN-DBS.

脳神経外科



Theme of research:

Assessment of cerebral ischemia by oxygen pulse-based near infrared optical

topography


Eiju Watanabe

Takehiko Konno

Toshihiro Mashiko


SPECT and angiography are methods used to assess the cerebral blood flow dynamics;

however they have several drawbacks such as physical stress on the patients and

invasiveness. In order to overcome these drawbacks, we proposed an alternative method

of using optical topography (OT).

We used a 48-channel OT system with 2 faces of 3×5 probe-holders on the patient’s

head covering the bilateral front-temporal areas. Measurements were performed at a

frequency of 10Hz. The subjects inhaled room air followed by oxygen for 2 minutes

and then room air again, and SpO2 were monitored at the subjects’ finger tips.

The level of oxy-hemoglobin measured by OT in normal brain regions showed a

trapezoid increase in accordance with oxygen inhalation, and similar results were

obtained for SpO2. In the ischemic regions, the oxy-hemoglobin increase was delayed

and/or its height was lowered. These observations suggest that transmission of the

systemic SpO2 wave pattern was delayed and lowered in the ischemic region; this

phenomenon can be utilized to detect cerebral ischemia. Our results suggested that the

regional attenuation of the oxy-hemoglobin wave reflects the ischemic state of cerebral

blood flow.

This method uses oxy-hemoglobin as a tracer of OT. It can be clinically utilized as a

real time and noninvasive assessment method for the assessment of cerebral ischemia.

整形外科学


Department of Orthopaedics

Theme of research:

Patient-based outcome measures for spine surgeries


Atsushi Kimura, M.D., Ph.D., [email protected]



Over the past decade, there has been increasing interest in the use of patient-based measures of

medical care. Patient-based measures include generic measures, disease-specific measures, and

measures of patient satisfaction. We prospectively investigate patient-based outcomes in patients

undergoing various spine surgeries. In particular, we are interested in chronic pain before and after

spine surgeries.

産科婦人科学


Department of Obstetrics and Gynecology

Theme of research:

Basic and clinical researches are under way in the three divisions: 1) Oncology, 2) Obstetrics, and 3)

Reproductive Endocrinology.


Matsubara S (chairman and professor), 1) Oncology: Fujiwara H (professor), Konno R (professor), Saga S (associate professor), Takei Y(assistant professor), Machida S(assistant professor), 2) Obstetrics: Matsubara S (professor), Okuchi A (associate professor),Watanabe T (associate professor), Usui R(associate professor), Kuwata T(associate professor), 3) Endocrinology: Suzuki T(associate professor)


The followings are under way.

1) Oncology: The basic and clinical researches have been performed for the gynecologic malignancies,

including ovarian and cervical cancers. As for ovarian cancer, we have been trying some new cancer

therapies such as the molecular targeted therapies in which the angiogenetic factors like VEGF, etc. are

suppressed for the purpose of anti-tumor effects and inhibition of the peritoneal dissemination, and in

addition the gene therapies in which the anti-angiogenetic agents, including HGF/NK4, soluble Flt-1,

etc. are supplied systemically by use of the adeno-associated vectors (AAV). In cervical cancer, to

establish the gene therapy targeted to E6. E7 proteins, we developed a model mouse using a cervical

cancer cell line, and we evaluated the therapeutic efficacy of AAV-based vector to suppress the E6, E7

proteins.

2) Obstetrics: To elucidate the relationship between cytokines/growth factors and the pathophysiology

of gestational hypertension. To characterize the blood coagulation mechanism in pregnant women. To

evaluate the maternal-fetal well-being by ultrasound. To establish the prediction method for the

occurrence of gestational hypertension. To characterize the relationship between maternal vaginal

bacterial flora and preterm delivery. To establish procedures to achieve hemostasis for postpartum

bleeding. To establish surgical technique for cesarean section for placenta previa.

3) Reproductive Endocrinology: anti-gamete immunity: analysis of the roles of anti-sperm or anti-zona

pellucida antibodies in fertilization and embryo development. sperm physiology: investigation of the

mechanism of sperm capacitation. Tubal infertility: study for the roles of several chemokines in

Chlamydia infection. IVF and ICSI: improvement of the fertilization rates and TLRS. Development of

minimally invasive surgery: ovarian drilling using transvaginal hydrolaparoscopy.

腎臓外科学


Division of Renal Surgery and Transplantation, Department of Urology

Theme of research:

1. Renal transplantation/Transplant immunology 2. Vascular access surgery for hemodialysis 3. Renal hyperparathyroidisms 4. Minimally invasive adrenal/renal surgery 5. Renal cell cancer in hemodialysis patients


1. Takashi Yagisawa, MD, PhD, Professor 2. Koji Nanmoku, MD, PhD, Assistant Professor 3. Takaaki Kimura, MD


1. Renal transplantation/Transplant immunology (clinical and basic researches) (a) 2~3 renal transplants performed in a month (b) Trial and evaluation of new immunosuppressive drugs (c) ABO blood type incompatible transplantation (d) Transplant organ tolerance (e) Advanced surgical techniques such as vascular anastomosis and laparoscopic donor

nephrectomy (f) Oppotunistic infections such as cytomegalovirus and EB virus after transplantation (f) Oxalate and calcium metabolism in renal transplant and hemodialysis patients)

2. Vascular access surgery for hemodialysis and peritoneal access surgery for CAPD: (a) 150~200 vascular access surgery performed in a year (b) Advanced techniques using artificial vascular devices 3. Secondary hyperparathyroidisms in dialysis patients (a) 3-4 parathyroid surgery performed in a month (b) Relationship between the grade of hyperplasia and calcium sensing receptor 4. Minimally invasive adrenal/renal surgery (a) Advanced retroperitoneoscopic surgery for adrenal tumor and renal cancer (b) Retroperitoneoscopic (laparoscopic) donor nephrectomy

5. Renal cell cancer in hemodialysis patients (a) Pathogenesis of renal cell cancer in dialysis kidneys (compared to cases with normal

renal function.)

泌尿器科学部門


Department of Urology

Theme of research:

Heterogeneity of bladder cancer


Tatsuo Morita, Professor


Heterogeneity of bladder cancer has been well documented with respects to biologic, cytogenetic, and histologic properties. These evidences suggest the clonal evolution which can sometimes be seen as heterogeneity within the tumor mass as the tumor grows. Namely, in the process of tumor progression, acquisition of genetic alterations results in divergent clones with heterogeneity in genotypes and phenotypes. We previously reported that human bladder cancer cell line JMSU1 established from malignant ascetic fluid in advanced bladder cancer patient showed morphological heterogeneity at the initial culture in vitro. Therefore, JMSU1 at the first passage seems to contain divergent clones which would reflect the clonal evolution developed during the tumor progression in the bladder cancer patient. The purposes of our project are to establish the clones from the first passage of human bladder cancer cell line JMSU1 to examine clonal heterogeneity in terms of genotypes and phenotypes, and to evaluate the divergent clonal evolution in the process of tumor progression.

耳鼻咽喉科学


Department of Otolaryngology-Head and Neck Surgery

Theme of research:

Head and Neck Cancer

１：Biology of Cancer Cells

２：Identification of Cancer Stem Cells

３：Clinical Trial


Hiroshi Nishino, Professor, e-mail: [email protected]


１：Biology of Cancer Cells

We have studied a biology of cancer cells. Especially IL-6 enhances invasion of cancer cells. Now we study an affect of cytokines on a proliferation and invasion of cancer cells.

２：Identification of Cancer Stem Cells

An exist of head and neck cancer stem cells is little known. Biology of head and neck cancer stem cells is also unknown. Now we have tried an identification of head and neck cancer stem cells. An immunohistological approach is now going. In the near future we will investigate a FACS method and study biology of cancer stem cells.

３：Clinical Trial

Voice, phonation, swallowing and visual acuity is very important on a quality of patients` life. Many head and neck patients are not satisfied while they manage a daily life after treatments. We have study a platinum based concurrent chemoradiation and a cetuximab based bio-radiation for advanced head and neck cancer patients.

耳鼻咽喉科学


Department of Otolaryngology/Head and Neck Surgery

Theme of research:

#1 Signal transduction in Head and Neck Squamous Cell Carcinoma #2 Gene therapy for Head and Neck Squamous Cell Carcinoma


Takeharu Kanazawa, Associate Professor: [email protected]


Galanin and its receptors, GALR1 and GALR2, are known as tumor suppressor and focused as therapeutic targets in head and neck squamous cell carcinoma (HNSCC). Previously, we demonstrated that the function of signaling pathways of GALR1 and GALR2. In HNSCC cells with silenced GALR1 and GALR2, we showed that reexpressed GALR1 suppresseed tumor cell proliferation via the extracellular-regulated protein kinase-1/2 (ERK1/2) -mediated effects on the cyclin-dependent kinase inhibitors (CKI) and cyclinD1. On the other hands, in the GALR2-transfected HNSCC cells, galanin suppressed proliferation and induced apoptosis. Galanin stimulation also mediated decreased expression of cyclin D1 and increased expression of the CKI, p27Kip1 and p57Kip2. These effects were similar to GALR1, but GALR2 also induced caspase-3-dependent apoptosis, which was confirmed by Annexin-V staining and DNA fragmentation analysis. Thus, we understood the function of GALR1 and GALR2 as tumor suppressor, but the signaling pathway of GALR2 is still unclear. Our search is currently focused on signal transduction of GALR2 and suicide gene therapy for HNSCC using GALRs and adeno-associated virus vector.

（小児）耳鼻咽喉科


Pediatric Otolaryngology Jichi Children’s Medical Center Tochigi

Theme of research:

Development of auditory central nervous system


Makoto Ito M.D.Ph.D Professor. [email protected]


Anatomical plasticity of projections of central auditory system have been examined to determine

the effects of unilateral or bilateral deafness during early development.

眼科学


Department of Ophthalmology

Theme of research:

1．Innovation of the treatments for intraocular inflammation (uveitis) 2．Pathogenesis and Treatment of Pterygium

Histopathologic Study of Meibomian Gland Dysfunction Aging Research of Lacrimal Gland

3．Strabismus, Amblyopia 4．Cytokine profiling of the aqueous humor from patients with age-related macular degeneration,

retinal vein occlusion and diabetic retinopathy.


1．Hidetoshi Kawashima, MD. & PhD., Professor & chairman, [email protected] 2．Hiroto Obata, Associate Professor, [email protected] 3．Shinji Makino M.D., PhD., [email protected] 4．Hidenori Takahashi M.D., Ph D., Associate Professor, [email protected]


1．We are exploring new modalities, both medical and surgical, of the treatments for intraocular inflammation (uveitis). We are in the process of standarizing monoclonal antibody therapy (infliximab) for Behcet’s disease. Furthermore, surgical intervention conducted and evaluated here includes transplantation of corticosteroid implants and vitrectomy for various complications such as cystoid macular edema, epiretinal membrane, and so forth.

2．Clinical research of strabismus and amblyopia based on binocular visual function. *Prismatic treatment for infantile esotropia

*Long-term outcome of strabismus surgery

*Management of dissociated vertical deviation

*Rotatory fusion in superior oblique muscle palsy *Abnormal head position in vertical strabismus

3．To optimize the treatment of age-related macular degeneration, retinal vein occlusion and diabetic retinopathy, we are examining multiplex cytokine assay of the aqueous humor or the vitreous fluid from patients. We already have over one thousand samples of the aqueous humor or the vitreous fluid from those patients and cataract or epiretinal membrane surgery patients as a control. Recent study demonstrated that VEGF concentration of the aqueous humor from cataract surgery patients without posterior vitreous detachment is twice as high as those with posterior vitreous detachment.

麻酔科学


Department of Anesthesiology and Critical Care Medicine

Theme of research:

1) The mechanism of acupuncture on central nervous system

2) Clinical and experimental study on the spinal canala endoscopy


1) Hideaki Tamai, Graduate fellow, [email protected]

2)Takashi Igarashi, Associate Professor, [email protected]


1) Investigation of effects of acupuncture on CNS by animal model and clinical case study.

2) The study of the spinal canal endoscopy includes (1) clinical investigation in patients with

Refractory back pain and (2) experimental study on developing a new product using a swine.

集中治療医学


Division of Intensive Care, Department of Anesthesiology & Intensive Care Medicine

Theme of research:

Sleep deprivation and delirium in critically ill patients.


Shin Nunomiya, MD. Professor and Director: [email protected]


Critically ill patients, especially being under mechanical ventilation, often suffer from severe sleep deprivation, which can lead to the development of impaired cognitive function, delirium. Since delirium itself is one of the independent risk factors of poor outcome of patients in ICU, efforts that prevent and avoid the development of delirium would have supreme importance for critically ill patient’s care. Moreover, early detection of delirium and proper intervention should be done to make an improvement of intensive care quality.

集中治療医学



Theme of research:

Clinical features and early diagnosis of coagulopathy in patients with sepsis.


Kansuke Koyama, MD. Research Associate: [email protected]


Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic inflammation which is frequently associated with coagulopathy. Inflammation and coagulation may play a pivotal role in the pathogenesis of sepsis. Severe inflammation in sepsis leads to tissue factor mediated activation of coagulation, which results in widespread fibrin deposition, contributing the development of multiple organ dysfunctions. Therefore, sepsis-induced coagulopathy may have 3 aspects: 1) an exacerbating factor of systemic inflammation, 2) a vascular endothelial dysfunction as one of the sepsis-induced organ dysfunctions, and 3) the etiology of multiple organ failures in severe sepsis. However both diagnosis and treatment of septic coagulopathy have not been determined. We currently investigate the time course of hemostatic biomarkers in patients with sepsis to determine the cutoff values for the early diagnosis of septic coagulopathy. We plan to identify the indication and appropriate timing of therapeutic intervention for coagulopathy in patients with sepsis in future.

集中治療医学



Theme of research:

Mortality and Prognostic factors in Patients with Hematological Malignancies admitted to the Intensive Care Unit.


Shinshu Katayama, MD. Research Associate: [email protected]


Recently, mortality of critical ill patients, like severe sepsis and septic shock, who admitted to the ICU are decreasing. But mortality of hematological malignant patients is 40-50%, presented still high mortality. Nowadays, there are several studies described about mortality and predictable factor of ICU death in Europe, but there are few studies conducted in Japan. So, we aimed to investigate the mortality of hematological patient and evaluate prognostic factors in our hospital.

臨床検査医学


Clinical Laboratory Medicine

Theme of research:

Medical Ultrasound


Nobuyuki Taniguchi, Professor, [email protected]


We have been researched for over 10 years of ultrasonic tissue characterization, which is the method to measure the ultrasonic properties of the human tissues. The measurements of frequency-dependent attenuation, scatter intensity, and non-linear parameter were already reported. The flow volume measurement, which is our original system, is another title for our research. The flow volumes of the common carotid arteries by age and sex were measured, and the variations by the examiners were estimated. Renal arterial flow volume is our recent work using this method, which cover not only normal but also diseased, which are compared with the measurements of conventional method. This system has already equipped with the commercialized machine. Now recent target we have is how can we make the comfortable ultrasound machine system. To make examination easily, we made new bodymarker system that demonstrate the position and direction of the transducer automatically. This system enable us to save examination time in abdomen, neck and breast area. This system is applied to transvaginal scan.

臨床検査医学


Department of Clinical Laboratory Medicine

Theme of research:

A study on serum amyloid A protein


Toshiyuki Yamada, Professor, [email protected]


Serum amyloid A (SAA) is an acute phase reactant, an apolipoprotein in HDL, and a plasma precursor of reactive amyloid fibrils. Researches are focused on the followings. i) The real function of SAA in physiological or inflammatory states. ii) The mechanism that SAA forms amyloid fibrils. iii) The influence of SAA on lipoprotein metabolism as a HDL apoprotein. iv) The merit of SAA as a clinical test.

臨床検査医学



Theme of research:

The development of tests for lipids and lipoproteins


Kazuhiko Kotani, Associate Professor [email protected]


The laboratory assessment of atherosclerosis in lifestyle-related diseases, such as dyslipidemia, obesity, and diabetes mellitus, is important. We have developed the atherosclerosis assessments using several novel tools, such as serum markers of oxidized or inflammation-modified LDL and HDL particles. Presently, to elucidate the clinical significance of the new oxidized LDL and HDL on lifestyle-related diseases is in progress in our group. The comparison of these new tools and traditional ones is a research topic. A final goal of these developments is a contribution to the prevention and management of atherosclerosis.

臨床検査医学



Theme of research:

①Risk of Bacterial Transmission by Ultrasonographic Probes

②Destructive influence on bacterial biofilm by ultrasonic irradiation


Harumi Koibuchi, MD,PhD, Lecturer


①Ultrasound probes can transmit bacteria from patient to patient. And bacterial

transmission can be almost completely prevent by wiping ultrasound probes with ethanol-soaked paper towel. But disinfection with ethanol may cause degradation of ultrasound probes.

② Bacterial biofilms can cause the intractable infectious disease, particularly, in patient

who is inserted medical implant such as central venous catheter, urethral catheter and ventilation tubes. Biofilms are composed of polysaccharides, proteins, and other nutrients essential for microbial survival. Once biofilm is formed, antibiotics don’t work well on bacteria covered by biofilm. On the other side, ultrasonic irradiation have an influence in chemical and biological on cell lines. We have investigated destructive influence on bacterial biofilm by ultrasonic irradiation. Some power of ultrasound can decrease in quantity of biofilm formed from Staphylococcus epidermidis.

臨床検査医学



Theme of research:

Ultrasound image recognition and tissue characterization


Kei KONNO, Associate Professor, [email protected]


Ultrasound imaging is essential for modern medicine. It gives us a lot of information about a patient through many kinds of image such as B-mode, Doppler and contrast enhanced images. Among them, B-mode is the most important in the clinical setting, and we usually make a diagnosis based on graphical patterns observed in B-mode image. However, it includes more precise information about underlying tissue as a minute change in echo texture (speckle pattern), which is recognized subjectively by some experts but hard to be assessed objectively. To extract such information from B-mode image by using various methods used in the field of image recognition may lead to an innovation in ultrasound tissue characterization.

臨床検査医学



Theme of research:

The examinations of atherosclerosis and vascular Disease using physiological methods


Kazuhiko Kotani, Associate Professor, [email protected]


We research about non-invasive vascular examinations. For the development of clinically useful methods to measure atherosclerotic conditions, we compare new non-invasive methods with existing methods such as flow mediated dilation and arterial thickness ultrasonically measured and pulse wave velocity.

臨床検査医学



Theme of research:

Vascular function and atherosclerosis


Michiaki Miyamoto, Research Assistant


We study vascular function and atherosclerosis in subjects with diabetes and dyslipidemia mainly

using ultrasonography, devices for measuring arterial stiffness or endothelial function, and

biomarkers.

臨床検査医学

Department/Division: Department of Clinical Laboratory Medicine

Theme of research:

Mineralocorticoid and salt in kidney disease

Klotho-FGF23 axis in kidney disease


Yoshitaka Iwazu, Lecturer, [email protected]


Renal fibrosis especially tubulointerstitial fibrosis is the final common pathway leading decreased

renal function. Salt or phosphate overload might induce tubular injury and interstitial fibrosis.

Researchers are focus on the followings.

i) Mechanisms of tubulo-intersititial fibrosis in mineralocorticoid/salt-induced hypertensive rats.

ii) Which of mineralocorticoid and salt mainly contributes to tubulointerstitial injury?

iii) Klotho-FGF23 axis as therapeutic target.

歯科口腔外科学


Oral and Maxillofacial Surgery

Theme of research:

1. Functional reconstruction of jaws after resection of oral cancer

2. Nature elucidation of disease in oral mucosa and new therapy.

3. Restoration of oral functions (chewing, speaking, swallowing) of cancer patients after surgery.


Yoshiyuki Mori, Professor, [email protected]

Yoshinori Jinbu, Professor, [email protected]

Tadahide Noguchi, Assistant Professor, [email protected]


1. We investigate immediate functional reconstruction. Especially ''Bare bone graft'' after resection

of mandibular cancer.

2. We intend to elucidate the nature of various diseases in oral mucosa, classify diseases correctly

and establish new treatment procedure.

3. After resection on oral cancer, many patients lose oral functions such as chewing, speaking and

swallowing. We intend to evaluate the abilities of each patient, investigate the cause of those

defects and establish new rehabilitation programs.

4. Developing and evaluation of new approach of orthognathic surgery using distraction

osteogenesis in patients with severe maxillary and/or mandibular deformity.

救急医学


Emergency & Critical Care Medicine

Theme of research:

Emergency Medical System


Masayuki Suzukawa, Professor, [email protected]


Japanese emergency medical system has a long history but the system itself has been tired out and does not fit for new modern society and new technology. We are proposing the medical control system for the pre-hospital care and examining the efficacy of various components of medical control system, such as medical director governance, educational system for paramedic, efficient use of ambulance cars, and systematic and practical classification of emergency patients. Recently, we are working on the project of introducing First Responder system to Japan.

地域医療学


Division of Community and Family Medicine, Center for Community Medicine

Theme of research:

1. Rural health 2. Community-based epidemiology


Professor Eiji Kajii MD, PhD, [email protected]

Professor Masami Matsumura MD, PhD, [email protected]

Professor Soichi Koike MD, PhD, [email protected]

Professor Shizukiyo Ishikawa MD, PhD, [email protected]

Professor Toyomi Kamesaki MD, PhD, [email protected]

Associete Professor Junichi Mise MD, [email protected]


1. Rural health

Rural Health System in Japan and Rural Medical Education

・Nakamura, T., Okayama, M., Aihara, M., Kajii, E.: Injury mortality and accessibility to emergency care in Japan : an

observational epidemiological study. Open Access Emergency Medicine 6: 27-32, 2014.

・Takamura, K., Okayama, M., Takeshima, T., Fujiwara, S., Harada, M., Murakami, J., Eto, M., Kajii, E.: Influence of

salty food preference on daily salt intake in primary care. International Journal of General Medicine 7:205-210, 2014.

・Takezako, Y., Ishikawa, S., Kajii, E.: Advance Directives in Japanese Nursing Homes. Journal of Pain Symptom

Management. 45: 63-70, 2013.

・Harada, M., Okayama, M., Ae, R., Kojo, T., Aihara, M., Kajii, E.: A Study on Regional Disparities in Access to

Inpatient Care, Using the Gini Coefficient. General Medicine 13(1): 25-29, 2012.

・Morita, Y., Kuroki, S., Lefor, A., Kajii, E.: Analysis of the Reasons for Visits to a Clinic on an Isolated Island. General

Medicine 13(1): 30-36, 2012.

・Muramatsu, S., Aihara, M., Shimizu, I., Arai, M., Kajii, E. : Current Status of Kampo Medicine in Community Health

Care. General Medicine 13(1): 37-45, 2012.

2. Community-based Epidemiology

・Hirose, H., Ishikawa, S., Gotoh, T., Kayaba, K., Kajii, E.: Lifestyle Risk Charts Illustrating the 10-year Risk of Death

in a Japanese Small Community: The JMS Cohort Study at Wara. 自治医科大学紀要 36：57-62，2014．

・Ishikawa, J., Ishikawa, S., Kario, K., the JMS Cohort Study Inverstigator Group: Relationships between the QTc

interval and cardiovascular, stroke, or sudden cardiac mortality in the general Japanese population. Journal fo

Cardiology Jul 24, 2014 ( pii: S0914-5087 (14) 00160-9. doi.org/10.1016/j.jjcc.2014.05.008).

・Kakehi, E., Kotani, K., Ishikawa, S., Goto, T., Kayaba, K., Nakamura, Y., Kajii, E.: Relationship between screening

plasma glucose concentrations and cancer-and all-cause mortality: the Jichi Medical School(JMS) cohort study. Journal

Public Health 22: 505-511, 2014 ( doi: 10. 1007 / s10389-014-0643-6).

・Kaneda, Y., Ishikawa, S., Gotoh, T., Kayaba, K., Yasuda, K., Kajii, E.: Risk of Cerebral Infarction assessed by Fasting

Insulin and Fasting Glucose in a Japanese General Population: The Jichi Medical School Cohort Study. 自治医科大学

紀要 36: 33-40, 2014.

・Yamamoto, R., Ishikawa, S., Mizooka, M., Kajii, E.: The prevalence of Helicobacter pylori with hypertension: The

地域医療学

JIchi Medical School Cohort Study. Jichi Medical University Journal 35:13-18, 2013.

・Yano, Y., Kario, K., Ishikawa, S., Ojima, T., Gotoh, T., Kayaba, K., Tsutsumi, A., Shimada, K., Nakamura, Y., Kajii, E.

and The JMS Cohort Study Group : Associations Between Diabetes, Leanness, and the Risk of Deaths in the Japanese

General Popuraton: The JIchi Medical School Cohort Study. Diabetes Care Dec 18, 2012 (Epub ahead of print).

・Ishikawa, S., Kotani, K., Kario, K., Kayaba, K., Gotoh, T., Nakamura, Y, Kajii, E. and The JMS Cohort Study Group :

Inberse association between serum lipoprotein(a) and cerebral hemorrhage in the Japanese population. Thromb Res.

Epub Dec.20, 2012.

・Sawabe, M., Tanaka, N., Mieno, MN., Ishikawa, S., Kayaba, K., Nakahara, K., Matsushita, S.; JMS Cohort Study

Group : Low lipoprotein(a) concentration is associated with cancer and all-cause deaths: a population-based cohort

study (the JMS cohort study). PLoS One. 7(4):e31954. Epub 2012 Apr 2, 2012.

・Baba, Y., Ishikawa, S., Amagi, Y., Kayaba, K., Gotoh, T., Suzuki, M., Kajii, E.: Cardiovascular disease risk factors and

menopausal status: a study of 2467 Japanese women as part of the Jichi Medical Cohort Study. General Medicine.

2012; 13 .

・Yamamoto R, Ishikawa S, Mizooka M, Kajii E. and JMS Cohort Study: Helicobacter pyirori Infection and

High-density Lipoprotein Cholesterol in Japanese Women; the JMS Cohort Study. General Medicine 13(2): 93-102,

2012.

3. Others

・Nakashima, Y., Kenzaka, T., Okayama, M., Kajii, E.: A case of thyroid storm with cardiac arrest. International Medical

Care Reports Journal 7: 89-92, 2014.

・Kenzaka, T., Okayama, M., Fujiwara, S., Takeshima, T., Kumada, M., Kamesaki, T., Eto, M., Harada, M., Takamura,

K., Kajii, E. and The Jichi Community Genetics Team.: Analysis of regional differences in the expression frequency of

salt-sensitive genes in Japan. Experimental & Clinical Cardiology 20(10): 6523-6536, 2014.

・Takeshima, T., Kumada, M., Mise, J., Ishikawa, Y., Yoshizawa, H., Nakamura, T., Okayama, M., Kajii, E. : Reasons

for encounter and diagnoses of new outpatients at a small community hospital in Japan: an observational study.

International Journal General Medicine 7: 259-269, 2014 (Jun 5;7:259-69. doi: 10.2147/IJGM.S62384. eCollection

2014).

・Matsumoto, M., Koike, S., Matsubara, S., Kashima, S., Ide, H., Yasunaga, H.: Selection and concentration of obstetric

facilities in Japan: Longitudinal study based on national census data. Journal of Obstetries and Gynaecology Research

July 2, 2014 (doi: 10.1111/ jog.12663).

・Takeshima, T., Okayama, M., Harada, M., Ae, R., Kajii, E.: Effects of disclosing hypothetical genetic test results for

salt sensitivity on salt restriction ehavior. International Journal of General Medicine. 6: 361-368, 2013.

・Okayama, M., Takeshima, T., Ae, R., Harada, M., Kajii, E.: Primary care patient willingness for genetic testing for

salt-sensitive hypertension: a cross sectional study. BMC Family Practice 14: 149, 2013.

・Nakashima, Y., Harada, M., Okayama, M., Kajii, E.: Analgesia for pain during subcutaneous injection: effectiveness of

manual pressure application before injection. International Journal of General Medicine 6: 817-820, 2013.

・Takezako, Y., Ishikawa, S., Kajii, E.: Advance Directives in Japanese Nursing Homes. Journal of Pain and Symptom

Management Epub Aug 25, 2012.

・Kenzaka, T., Okayama M., Kuroki, S., Fukui, M., Yahata, S., Hayashi, H., Kitao, A., Kajii, E., Hashimoto, M.: Use of

a semiquantitative procalcitonin kit for evaluating severity and predicting mortality in patients with sepsis. International

Journal of General Meicine 5: 483-488, 2012.

地域医療学

・Kenzaka, T., Okayama, M., Kuroki, S., Fukui, M., Yahata, S., Hayashi, H., Kitao, A., Sugiyama, D., Kajii, E.,

Hashinomo, M.: Importance of Vital Signs to the Early Diagnosis and Severity of Sepsis: Association Between Vital

Signs and Sequential Organ Failure Assessment Score in Patients with Sepsis. Internal Medicine 51: 871-876, 2012.

・Kenzaka, T., et al. : Importance of vital signs to the early diagnosis and severity of sepsis: association between vital

signs and sequential organ failure assessment score in patients with sepsis. Intern Med. 2012; 51: 871-876.

分子病態研究部


Division of Cell and Molecular Medicine, Center for Molecular Medicine

Theme of research:

Understand life by light


Satoshi Nishimura, MD, PhD, Professor, [email protected]


In the physiological and pathological conditions, complex cellular interplay takes place in living animals. However, conventional microscope approach using two dimensional analysis was not sufficient for analyzing in cell dynamics and functions in vivo. Thus, we improved in vivo imaging technique by custom-designed two photon microscopy, and multi-color cytometry system for metabolic and thrombotic disease evaluation. In this system, we identified single blood cells in circulating vessels, and we combined intravital visualization and light-based cell manipulation to reveal the multicellular processes in diseased conditions. Research field is very broad. Please refer to our recent papers as bellows: Thrombus and platelet : Nishimura et al, 2012 Blood. Nishimura et al, 2010 JCI. Thrombopoiesis : Nishimura et al, 2015 J Cell Biology. iPS and platelet : Takayama, Nishimura et al. 2012 J Exp Med. Nakamura, Nishimura et al. 2014 Cell Stem Cell. Metabolic Diseases : Nishimura et al, 2007 Diabetes. Nishimura et al, 2008 JCI. Nishimura et al, 2009 Nat Med. Nishimura et al, 2013 Cell Metabolism Nishimura et al, 2014 Diabetes. Heart Diseases : Seo, Nishimura et al. 2015 Prog Biophys Mol Biol. Seo, et al. 2014 PNAS Seo, et al. 2014 Circ Res We are very welcome to foreign students with broad backgrounds: medicine, biology, engineering, informatics, and optics. Communicating with English is okay in my labs. You can freely access two-photon microscopy systems and understand life directly.

幹細胞制御研究部


Division of Stem Cell Regulation, Center for Molecular Medicine

Theme of research:

1) Stem Cell Biology 2) Molecular Genetics and Epigenetics of Cancer


1) Yusuke Furukawa, M.D., Professor of Medicine, [email protected] 2) Jiro Kikuchi, Ph.D., Associate Professor, [email protected] 3) Taeko Wada, Ph.D., Research Associate, [email protected]


1) We investigate the regulatory mechanisms of cell cycle and cell death of hematopoietic and cancer stem cells in order to provide the rational basis of safe and effective clinical application.

2) We attempt to clarify the underlying mechanisms of carcinogenesis and leukemogenesis by investigating the alterations of oncogenes and tumor suppressor genes at the genetic and epigenetic levels.

遺伝子治療研究部


Division of Genetic Therapeutics

Theme of research:

Gene transfer using various vectors, especially AAV vectors


Hiroaki Mizukami, MD, PhD, Professor, [email protected]


We have been working with Adeno-associated virus (AAV) vectors, which have ideal features for human gene therapy. As for the basic research of AAV vectors, utility of AAV serotypes and various cis-elements have been systematically evaluated. We have also optimized conditions concerning AAV-mediated RNAi in order to knockdown gene expression in vivo. Moreover, we have established assay systems to measure immune responses related to gene transfer and expression. Notably, assay system for neutralizing antibody (NAb) has been sufficiently improved for preclinical and clinical studies. Based on these basic research activities, we are exploring possible applications of AAV vector- mediated gene therapy in the following categories. (I) Neurological disorders: We have demonstrated a large number of applications using AAV-mediated gene transfer into various locations of central nervous system, from mice to humans. In a series of studies against Parkinson’s disease, after success with animal models, a clinical trial has been performed successfully (Joint research with the Division of Neurology and the Department of Neurosurgery). (2) Genetic disorders: One of the most important candidate disease in this category is hemophilia, especially hemophilia B. We demonstrated long-term expression of factor IX in the therapeutic level following intravenous vector injection in monkeys. Careful selection by NAb status is essential before enrolling the study, suggesting the importance of the NAb screening in the future human trials (Joint research with the Division of Cell and Molecular Medicine). (3) Eye diseases: Retina is a good target for AAV-mediated gene transfer. We demonstrated the efficacy of soluble flt gene transfer to prevent disease progression in diabetic retinopathy in a rat model (SDT rat). (4) Malignancy: Indirect cancer gene therapy by the suppression of tumor angiogenesis, metastasis, and dissemination are investigated. We developed a model mouse with lymphatic metastasis, and demonstrated suppression of lymphatic metastasis using gene therapy with AAV-sflt4 vectors targeting VEGF-C. These results, along with the success in this field worldwide, suggest that AAV-mediated gene transfer must play a crucial role in medicine in the near future.



Genetic Therapeutics

Theme of research:

Development of a novel reinforced adoptive immune-gene therapy for malignant lymphoma


Tomonori Tsukahara, PhD, Assistant Professor, [email protected]


We are focusing on developing a novel reinforced adoptive immune-gene therapy using genetically engineered autologous T lymphocytes expressing a chimeric antigen receptor targeting CD19, for the treatment of refractory B-cell malignant lymphoma. For pre-clinical studies, we are evaluating the ability of engineered T lymphocytes to recognize and kill CD19 positive-tumor cells in vitro and Xenograft mouse models. Futhermore, we are exploring new ways to improve the therapeutic efficacy of engineered T lymphocytes.



Division of Genetic Therapeutics

Theme of research:

Safe gene engineering of the human genome by a viral gene integration machinery


Masashi Urabe, Assistant Professor, [email protected]


The adeno-associated virus (AAV), a member of parvovirus has a unique property that it preferentially inserts its genome into the AAVS1 site on chromosome 19 (19q13.4), one of safe harbors for transgene insertion. The use of the AAV integration machinery enables AAVS1-specific insertion of a given DNA sequence. Insertion of foreign DNA to a defined site is prerequisite for safe genetic manipulation of human cells since random integration of foreign DNA, for example, by retrovirus vectors can give rise to insertional mutagenesis. iPS cells can be applied for a lot of therapeutics in regenerative medicine. However, forced reprogramming of somatic cells to generate iPS cells and their ability to proliferate indefinitely raises the concern about their oncogenic potential. If iPS cells have a suicide gene, iPS cells even after malignant transformation can be selectively eliminated by the simple activation of the suicide gene. We are currently developing iPS cells with a suicide gene at AAVS1. The use of iPS cells with a fail-safe system should accelerate clinical applications of iPS cells.

抗加齢医学研究部


Division of Anti-aging Medicine

Theme of research:

To understand molecular mechanisms of aging process


Hiroshi Kurosu,PhD.Associate Professor, [email protected]

Kazuhiro Shiizaki, MD,PhD. Lecturer, [email protected]

Makoto Kuro-o, MD,PhD. Professor, [email protected]


Our laboratory focuses on translating basic research on molecular mechanism of aging into

development of effective interventions in age-related diseases. We have identified novel endocrine

axes mediated by Klotho and FGF, which regulate mineral and energy metabolism. Our major

research interest is to establish the Klotho-FGF endocrine axes as novel targets for diagnosis and

treatment of chronic kidney disease.

再生医学研究部


Center for Molecular Medicine

Division of Regenerative Medicine

Theme of research:

Pigs, pigs, let them in for medical research!


Prof. Yutaka Hanazono, MD, PhD, [email protected]


Our laboratory has engaged on three projects.

1) The derivation of hematopoietic stem cells from human iPS cells: We are generating

hematopoietic stem cells from human iPS cells in vivo in large animals such as sheep and

mini-pigs in order to address the shortage of donors for hematopoietic stem cells.

2) Pig models: We are generating mini-pig models for human diseases, such as severe

combined immunodeficiency (SCID), which would more closely resemble humans.

3) Genome editing: We are genetically modifying mouse, pig, and human cells with

CRISPR/Cas9 to model or treat human diseases.

The projects all include pig matters! The use of pigs or sheep is a unique feature of our lab,

but conventional experimental animals such as mice are of course used. I would like to

invite foreign post-graduate students to participate in these projects. Please come and join

us!

炎症・免疫研究部


Division of Inflammation Research, Center for Molecular Medicine

Theme of research:

Role of the Inflammasome in Cardiovascular Disease and Metabolic Disorder


Masafumi Takahashi, Professor, E-mail: [email protected]


The major objective of my laboratory is to determine how inflammatory responses occur

in cardiovascular disease and metabolic disorder, and to development new treatments for

these diseases, including atherosclerosis, myocardial infarction, heart failure, diabetes,

nonalcoholic fatty liver disease (NAFLD), and hyperlipidemia. In particular, we are

currently focusing on a newly discovered innate immunenity pathway known as the

“inflammasome”. Our group recently found that the inflammsome plays an important role

in the pathophysiology of vascular injury, atherosclerosis, and myocardial infarction, and

demonstrate that the inflammasome acts as an initial sensor for the sterile inflammatory

response in cardiovascular disease.

細胞生物研究部


Division of Biology, Center for Molecular Medicine

Theme of research:

Animal models for genetic diseases


Kiyoshi Kawakami, Professor Hiroshi Yajima, Assistant Professor Shigeru Sato, Associate Professor Hiroki Sugimoto, Assistant Professor Masanori Takahashi, Assistant Professor


By using inheritable genetic manipulation technique, we have developed several animal

models of human diseases. One is Na,K-ATPase (sodium pump) alpha subunit gene

knockout mouse, and the other is Six gene knockout mouse.

The sodium pump is the enzyme responsible for the maintenance of Na+ and K+ gradients

across the cell membrane. Adult mice heterozygous for the alpha2 subunit mutation

showed augmented fear/anxiety behaviors and late-onset hyperphagia, emphasizing those

heterozygous mice to be the model animal for lifestyle diseases. In addition, mutations of

a2 subunit gene are causative for familial hemiplegic migrane (FHM2). Mice harboring

mutations found in the patients have been established and are currently investigated

whether they are useful for disease model. We have recently established alpha3 subunit

knock out mice. The α3 subunit gene mutation is related to rapid-onset Dystonia

Parkinsonism (RDP). We have been elucidating whether the knockout mouse is an animal

model for RDP.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant developmental disorder

characterized by the association of branchial arch defects, hearing loss, and renal

anomalies. It is recognized as one of the common forms of autosomal dominant hearing

impairment. Mutation in Six1 as well as Six5 were identified as causes of BOR. Mice

homozygous for Six genes mutation (Six1, Six4, and Six5) showed various defect in

development of sensory organs, cranial ganglia, and kidney. We will focus how Six gene

product regulate sensory organ formation.




Theme of research:

Roles of Six genes in organogenesis


Hiroshi Yajima, Assistant Professor Shigeru Sato , Associate Professor Kiyoshi Kawakami, Professor Masanori Takahashi, Assistant Professor


Organogenesis is a precisely orchestrated process that is directed by the cell-intrinsic and

-extrinsic cues. Genetic ablation of Six1 and Six4 genes in mice caused multiple defects in

development of various organs; olfactory epithelium, inner ear, cranial ganglia, spinal

ganglia, skull, jaw, tongue, thymus, skeletal muscles, skeletons and kidneys. Since these

organs have different origins and architectures, Six genes should play distinct roles in each

organ formation. We explore common or specific functions of Six genes in the formation

of these organs, using molecular biological approaches, anatomical / histological analyses

and cell / tissue / organ / whole-embryo culture techniques.

We found aberrant primary sensory neuron-like cells within the spinal cord of Six1/Six4

double knockout mice. Since intramedullary sensory neurons are thought to be an

ancestral form of sensory neurons and not generated in the amniote, Six genes also appear

to be involved in the evolution of trunk sensory system.

Our final goal is to understand how do the same Six transcription factors play distinct roles

in different organogenesis and to get an evolutionary insight into the function and

regulation of Six genes.



Division of Biology

Theme of research:

Molecular and developmental mechanisms of placode formation


Shigeru Sato, Associate Professor, Kiyoshi Kawakami, Professor


Sensory placodes are ectodermal thickenings found in the head of vertebrate embryos that

give rise to cranial sensory organs (eye, nose and ear). Several transcription factors

including Six and Eya families are expressed in sensory placodes and in a common

precursor region for all placodes (PPR) and are essential for sensory placode formation.

Mice deficient for Six1 or Eya1 show severe malformation in the ear and nose while

mutations in human SIX1 and EYA1 are known to cause branchio-oto-renal (BOR)

syndrome. To understand the molecular and developmental mechanisms of sensory

placode formation, we have identified various placode-specific enhancers that activate Six

and Eya gene expressions by comparative genomics combined with in vivo enhancer

analyses using model animals. By using these enhancers as a tool, we are analyzing 1) the

gene cascade controlling PPR/placode formation, 2) the cell lineage of PPR and placodes,

3) the role of PPR/placode cells in the head development and 4) the evolutionary origin of

vertebrate placodes.




Theme of research:

Development of therapy for muscle dystrophy


Hiroshi Yajima, Assistant Professor Shigeru Sato , Associate Professor Kiyoshi Kawakami, Professor


Muscle satellite cells are known to play key roles in the skeletal muscle regeneration. To

understand how the proliferation and differentiation of muscle satellite cells are

orchestrated in order to regenerate the skeletal muscle, we are investigating the expression

and function of Six genes in the muscle satellite cells in vivo and in vitro.

The involvement of Six genes in the muscle regeneration has not been demonstrated,

although they have been shown to be required for the skeletal muscle development. The

expressions of Six1, Six4 and Six5 were maintained throughout the proliferation and

differentiation of muscle satellite cells isolated from the skeletal muscle of adult mice.

Overexpression of Six1 facilitated the differentiation of muscle satellite cells. In contrast,

overexpression of Six4 and Six5 inhibited the proliferation and differentiation of them.

The muscle satellite cells derived from Six4⁺/⁻ Six5⁻/⁻mutant mice were capable to

proliferate more rapidly than those from wile-type mice. There results suggest that Six

genes regulate the proliferation and differentiation of muscle satellite cells.

Our goal is to improve the symptoms of muscular dystrophy by manipulating the

expression of Six genes.




Theme of research:

Brain patterning and brain asymmetry


Masanori Takahashi, Assistant Professor, [email protected]


1) Subdividing the brain primordium into distinct regions is a crucial strategy to generate different

types of neurons and glial cells at precise positions in the embryonic brain. I study molecular and

cellular mechanisms of brain patterning and neuronal differentiation in the mouse/rat embryo

using the techniques such as whole embryo culture, electroporation for transferring exogenous

genes into brain progenitor cells, and confocal laser-scanning time-lapse imaging.

2) Regionalization of the brain and localization of the function at postnatal and adult stages are

also important issues in developmental neurobiology. To elucidate the question how functional

brain asymmetry is established in the mammalian brain, I am focusing on the relationship between

the left-right asymmetric gene expression and handedness identified by food-reaching tasks.

人類遺伝学研究部


Division of Human Genetics, Center for Community Medicine

Theme of research:

Genetic study of lifestyle-related diseases


Sadahiko Iwamoto (Professor; [email protected]) Kazuhiro Nakayama (Assistant Professor; [email protected])


We have established several human population genome resource banks, which were attached with the data of anthropometric and metabolic parameters. The genome banks were consisted with multiple Asian ethnic groups, Japanese, Mongolian, Chinese, Thai and Palauan. Using these genome banks, we are performing genetic-epidemiological analysis mainly through the SNP based population genetics and have succeeded in identifying candidate loci associated with lifestyle-related diseases. We are also performing molecular analysis about the genetic alteration, which is identified through the genetic study. In order to show whether the gene or SNP associated with lifestyle-related diseases results in a functional alteration, in vitro or in vivo gene transduction study is employed routinely.

公衆衛生学


Department of Public Health

Theme of research:

Epidemiology of intractable diseases in Japan


Yosikazu Nakamura, Professor, [email protected] Nobuko Makino, Associate professor, [email protected]


Epidemiologic studies on several intractable diseases have been conducted in Japan every year under financial support by the Ministry of Health, Labour and Welfare. Our department manages the data from those epidemiologic studies. Our research topics regarding descriptive epidemiology of the intractable diseases were described below; Neurofibromatosis Myasthenia gravis Primary sclerosing cholangitis Precocious puberty

公衆衛生学



Theme of research:

Epidemiology of prion diseases


Yosikazu Nakamura, professor, [email protected]


A research committee of prion diseases has been registered patients with prion diseases, such as Creutzfeldt-Jakob disease, in Japan since 1999. More than 100 patients a year, or about 90% of patients in this country, were registered. Our department plays a part of epidemiologic analyses of the data registered.

公衆衛生学



Theme of research:

Epidemiology of cardiovascular diseases


Shizukiyo Ishikawa, Associate professor, [email protected] Yosikazu Nakamura, Professor, [email protected]


Several early studies demonstrated the protective effect of light to moderate alcohol consumption on cardiovascular diseases. As part of JMS (Jichi Medical School) Cohort Study which has been conducted in twelve communities in Japan, association between alcohol consumption and risk of cardiovascular diseases were investigated. Alcohol consumption and risk of stroke revealed dose-response relationship, and modest alcohol consumption reduced the mortality from all causes.

公衆衛生学



Theme of research:

Epidemiology of cardiovascular diseases


Shizukiyo Ishikawa, Associate professor, [email protected] Yosikazu Nakamura, Professor, [email protected]


Dietary pattern analysis has emerged as a possible approach to estimate whole dietary behaviors of study subjects in nutritional epidemiologic studies. As part of JMS (Jichi Medical School) Cohort Study which has been conducted in twelve communities in Japan, association between dietary patterns and risk of cardiovascular diseases were investigated. In our previous study, dietary patterns were related to risk factors for cardiovascular diseases (blood pressure and cholesterol level). Further prospective study regarding cardiovascular diseases are in progress.

公衆衛生学



Theme of research:

Epidemiology of Kawasaki disease


Yosikazu Nakamura, Professor, [email protected]


Kawasaki disease is an acute systemic vasculitis of unknown etiology. Children aged 4 year or younger mainly suffered from this disease. The main purpose of the treatment for the disease is to prevent developing coronary artery abnormalities. Nationwide epidemiologic surveys on Kawasaki disease have been conducted in Japan almost every two years since 1970. The data from those surveys were maintained in our department. Our research topics regarding Kawasaki disease epidemiology were described below; Chronologic and geographic change of incidence rate of Kawasaki disease Mortality after suffering from Kawasaki disease Risk factors for coronary artery abnormalities Familial cases of Kawasaki disease Risk factors for treatment failure for Kawasaki disease

Documents

Jichi Medical Research Overview 2015