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The research team in the Inflammatory Diseases Laboratory at LiHS in 2013 was focused on studying mechanisms and therapeutic implications of TGF-β/Smad3-dependent microRNAs in the progression of end organ diseases including chronic kidney disease and cardiovascular disease. Our research contributions have unravelled the mechanism of TGF-β/Smad3-mediated tissue scarring via Smad3-dependent-dependent microRNAs. We found that TGF-β/Smad3 mediates tissue fibrosis by upregulating miR-21, miR-192, and miR-433, but downregulating miR-29. We have also developed a specific anti-miRNA therapy for chronic heart and kidney diseases by targeting these Smad3-dependent miRNAs. These advanced achievements have been well recognised internationally as demonstrated by a number of high impact publications in the top rank journals of the subject fields and by many internationally-invited lectures/seminars and higher quality presentations with 3 outstanding scientific awards by our students.

Based on these scientific findings, we have successfully licensed two patents on the new development of a combinational Traditional Chinese Medicine (TCM) by using the mixture of a Smad3 inhibitor Naringerin and a Smad7 agonist Asiatic acid (US 61/719,107) and a Smad3 inhibitor on treatment of tumours by targeting the TGF-β/Smad3-dependent cancer microenvironments (US61/719,114).

PIs: Hui-yao Lan (Li Ka Shing Institute of Health Sciences, Department of Medicine and Therapeutics)

Arthur Chung (Li Ka Shing Institute of Health Sciences)

Research Progress Summary:

113Technical Report on Research Programmes

2013 was a good year for us. Firstly, 3 PhD students had successfully passed the thesis defence and obtained the PhD degree. Secondly, our research outputs had successfully resulted in a renewal of GRF grant (HK$8.8M) and a GRF grant (HK$0.75M) in exploring a new pathway of macrophage-myofibroblast-transition (MMT) in organ scarring.

Most excitingly, we have developed a new research direction in renal fibrosis from the existing project of Smad3-dependent microRNAs into the long non-coding RNAs (lncRNAs). We expect to lead this area of research in the field of renal medicine internationally.

Recognitions:

Awards and Fellowships

Member’s Name Details

Yang Chen • Young Nephrologist Award - The International Society of Nephrology 2013

Lian Guang Yu • Outstanding Presentation Award - Department Research Day 2013

Zhou Li • Best Abstract Presentation Award - The 50th ERA-EDTA Congress, 2013

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Grants and Consultancy

Details Member’s Name Amount (HK$)

Research Grants Council (RGC) Collaborative Research Fund (CRF) (1/6/2013 - 31/05/2016)Title: Macrophage-Myofi broblast-Transition in organ fi brosis:

molecular and clinical implications

Hui-yao Lan 8,800,000

Research Committee Group Research Scheme (1/6/2013 - 31/05/2016)Title: Macrophage-Myofi broblast-Transition in organ fi brosis:

molecular mechanisms and clinical implications

Hui-yao Lan 750,000

Donation (1/04/2013 - )Title: The mechanism of cardiovascular fi brosis

Hui-yao Lan 105,860

The Chinese University of Hong Kong Matching Grant (1/6/2013 - 30/5/2017)Title: Teaching and research enhancement for Li Ka Shing

Institute of Health Sciences - (MG6)

Hui-yao Lan 21,279

115Technical Report on Research Programmes

TGF-β/Smad3-dependent lnRNAs in fi brosis

Copyright © 2012 Hui-yao Lan

1. Xie, C., Jiang, X. H., Zhang, J. T., Sun, T. T., Dong, J. D., Sanders, A. J., Diao, R. Y., Wang, Y., Fok, K. L., Tsang, L. L., Yu, M. K., Zhang, X. H., Chung, Y. W., Ye, L., Zhao, M. Y., Guo, J. H., Xiao, Z. J., Lan, H. Y., Ng, C. F., Lau, K. M., Cai, Z. M., Jiang, W. G., & Chan, H. C. (2013). CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer. Oncogene, 32(18), 2282-2291.

2. Lv, J., Huang, X. R., Klug, J., Fröhlich, S., Lacher, P., Xu, A., Meinhardt, A., & Lan, H. Y. (2013). Ribosomal protein S19 is a novel therapeutic agent in infl ammatory kidney disease. Clinical Science, 124(10), 627-637.

3. Li, X., Lan, H. Y., Huang, X. R., Zhang, C., & Jin, L. J. (2013). Expression profile of macrophage migration-inhibitory factor in human gingiva and reconstituted human gingival epithelia stimulated by Porphyromonas gingivalis lipopolysaccharide. Journal of Periodontal Research, 48(4), 527-532.

4. Liu, G. X., Li, Y. Q., Huang, X. R., Wei, L., Chen, H. Y., Shi, Y. J., Heuchel, R. L., & Lan, H. Y. (2013). Disruption of Smad7 promotes ANG II-mediated renal inflammation and fibrosis via Sp1-TGF-β/Smad3-NF.κB-dependent mechanisms in mice. PLoS One, 8(1), e53573.

5. Wang, J., Zhao, J., Chu, E. S., Mok, M. T., Go, M. Y., Man, K., Heuchel, R., Lan, H. Y., Chang, Z., Sung, J. J., & Yu , J . ( 2013 ) . I nh ib i to r y ro l e o f Smad7 i n hepatocarcinogenesis in mice and in vitro. The Journal of Pathology, 230(4), 441-452.

6. Wei, L. H., Huang, X. R., Zhang, Y., Li, Y. Q., Chen, H. Y., Yan, B. P., Yu, C. M., & Lan, H. Y. (2013). Smad7 inhibits angiotensin II-induced hypertensive cardiac remodelling. Cardiovascular Research, 99(4), 665-673.

7. Wei, L. H., Huang, X. R., Zhang, Y., Li, Y. Q., Chen, H. Y., Heuchel, R., Yan, B. P., Yu, C. M., & Lan, H. Y. (2013). Deficiency of Smad7 Enhances Cardiac Remodeling Induced by Angiotensin II Infusion in a Mouse Model of Hypertension. PLoS One, 8(7), e70195.

8. Liu, W., Li, X., Zhao, Y., Meng, X. M., Wan, C., Yang, B., Lan, H. Y., Lin, H. Y., & Xia, Y. (2013). Dragon (repulsive guidance molecule RGMb) inh ib i ts E-cadher in expression and induces apoptosis in renal tubular epithelial cells. Journal of Biological Chemistry, 288(44), 31528-31539.

9. Li, R., Chung, A. C., Dong, Y., Yang, W., Zhong, X., & Lan, H. Y. (2013). The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway. Kidney International, 84(6), 1129-1144.

Publications:

10. Chung, A. C., Dong, Y., Yang, W., Zhong, X., Li, R., & Lan, H. Y. (2013). Smad7 suppresses renal fibrosis via altering expression of TGF-β/Smad3-regulated microRNAs. Molecular Therapy, 21(2), 388-398.

11. Zhong, X., Chung, A. C., Chen, H. Y., Dong, Y., Meng, X. M., Li, R., Yang, W., Hou, F. F., & Lan, H. Y. (2013). miR-21 is a key therapeutic target for renal injury in a mouse model of type 2 diabetes. Diabetologia, 56(3), 663-674.

12. Chung, A. C., Yu, X., & Lan, H. Y. (2013). MicroRNA and nephropathy: emerging concepts. International Journal of Nephrology and Renovascular Disease, 6, 169-179.

13. Li, R., Lan, H. Y., & Chung, A. C. (2013). Distinct roles of Smads and microRNAs in TGF-β signaling during kidney diseases. Hong Kong Journal of Nephrology, 15(1), 14-21.

14. Meng, X. M., Chung, A. C., & Lan, H. Y. (2013). Role of the TGF-β/BMP-7/Smad pathways in renal diseases. Clinical Science, 124(4), 243-254.