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OT3BIBna AHccepxauHOHHyio pa6oxy TrojibKOBoM EicaxepHHbi HocH(J)OBHbi
na TCMV:«MEXAHH3MtI OOPMMPOBAfflW
COCTO^HHH MO3FA B OTBET HA BO3ZIEHCTBHEB ITPEHATAJIBHOM GHTOTEHE3E»,
npe^cxaBJieHHyio K samnxe Ha concKaHHe VHCHOH cxeneHHOHOJiornnecKHx nayK no cneuHajiBHOcxH 03.03.01 - (J}H3HOJiorHJL
AicrvajibHocTb TeMbi BbinojiHCHHOH paGoTbi. Pesyjibxaxbi
<J)opMHpoBaHHa naxoJiorHHecKHX cocxoflHHH Mosra B OXBCX Ha
rnnoKCHH B npeHaxajibHOM onxorenese nocxeneHHO npoacnaiox ZIJIH nac
HepapXHK) H npnopHxexti B cucxeivre Mo6HjiH3au;HH 4>H3HOJiorH4ecKHX pesepsoB
4>yHKi;HOHajibHi>ix CHCXCM opraHH3Ma. B ^aHHOM KonxeKcxe
pa6oxa E.H.TIOJIBKOBOH ^BJiaexcn nacxbio 4)yH^aMeHTaJTBHbIX
npoBO4HMtix cneuHajTHCxaMH B o6jiacxn KJICXOHHBIX OCHOB noBe^eHHa H HX
^esperyjiauHH UOR BJIH^HHCM He^ocxaxKa KHCJiopo^a. Ha a^eKBaxHbix
3KcnepHMeHxajibHbix MO^ejiax E.H.TiojibKOBa Hccjie^OBaua oco6eHHocxH
cHCxeMHbix, Me^KJiexoHHbix, KJiexoMHbix H MOJieKyjiHpHbix npoueccoB, jie^cauiHx B
OCHOBC napyuieHHH pasBHxna LJHC BCJIC^CXBHC npenaxajibHOH rnnoKCHH.
9KcnepHMeHxajibHoe HsyHenne MexaHH3MOB KOMnencauHH co cxopoHbi
LlJiC MJieiconHxaiomHx B oxsex na napyuieHHe KHCJiopcmnoro roMeocxasHca
opraHH3Ma npo/ioJi^caexcH B xenenHe MHOFHX AecaxHJiexHH 4)H3HOJIoraMH'
6HOXHMHKaMH H MOJieKyjiapHbiMH 6nojioraMH pasHHX cxpan. 3xo HanpaBJieHHe
HCCJie^oBaHHH HMeex Ba^noe (jiyimaMenxajibHoe 3HaneHHe, x. K. OHO 4>opMHpyex
u;eJiocxHoe npe^cxasjieHHe o MexaHH3Max a/janxauHH opraHH3Ma K AewcxEHK)
cxpeccopoB Ha pannnx 3xanax onxorenesa. BMCCTC c XCM MHorae Bonpocw,
KacaioHiHec^ HsyneHHa npoi^eccos 4>opMHpoBaHH^ H KOopAHHauHH oxHomeHHH B
CHcxeMax cna6^ceHHH KJICXOK M03ra KHCJiopo^oM ocxaioxca HeBbiacneHKbiMH H
xpeGyiox coBpeMCHHoro 3KcnepHMeHxajri>Horo nccjie^oBaHHfl.
B Hacxoamee speMa yGe^HxejitHo noKasano, HXO B npe- H nepHHaxajibHOM
OHXorenese MOJKHO Bbi^ejinxb nepno^H, xapaKxepH3yiomHecK
BOCnpHHMHHBOCXblO MO3Pa K pa3JIHHHbIM IXOBpe>K,aaK>mHM CJ)aKXOpaM.
HapymeHHfl, o6ycjioBJieHHbie fleHCXBHeM noBpe^KflaiomHX 4>aKxopOB B 3XH
KpHTHHecKne nepHo^bi pannero onxoreHcsa, Moryx npuBozmxb K BOSHMKHOBCHHIO
He xojibKo rpy6bix Aec^eKxos pasBuxwa (Bpo5K#eHHbie aHOMajiHH - ypOACXBa), HO H
MHOrOHHCJieHHblX 4>yHKIJHOHaJIbHbIX paCCXpOHCXB B .UeaxCJIbHOCXH KJieXOK,
opranoB H CHCXCM Bcero opraHHSMa. O^HHM us snanHMbix H pacnpocxpaHe'HHbix
4>aKxopoB OKasbraaexcfl rnnoKCHfl. FHnoKCHJi njio/ia HBJI^CXCH
H3 caMbix Hacxo BcxpeHaiomHXCH OCJIO^KHCHUH npH 6epeMCHHOCXH H po^ax
y nejioBCKa. MHBasuBHbie Hccjie^oBaHHH Mosra na >KHBoxHbix B
npenaxanbHOH H nepHHaxajibHOH rnnoKCHH Moryx ^axb
Maxepnaji fljia AHarnocxuKH ,aHC<j)yHKUHH y HOBOpo^c^eHHbix, a
B xo^e ^ajibHeiiHiero pasBHXHa MJiaAenueB. rioao6Hbie HCCJie^OBaHHH
HaMexHxb nepcneKXHBHbie noaxo/ibi ^JTS KOppHrapyiomeH xepannn.
pa6oxa E.M.TrojibKOBOH HanpaBJiena Ha peuieHHe 3xnx
sa^an, HXO CBH^exejibcxsyex o 6e3ycjioBHOH aKxyajibnocxH Bbi6paHHOH
xeMbi Hccjie^OBaHHS.
HavHHan noBHJiia HccjiejosanHH. B npe^cxaBJieHHOH pa6oxe BnepBbie
HSJio^enbi pesyjibxaxbi MHOFOJICXRHX KOMnjieKCHbix HCCjie^oBaHMH
^BuraxejibHbix, 3MouHOHajibHbix H KorHHXHBHbix HapyuienHH noBe^eHHfl
3KcnepHMeHxanbHbix ^CHBOXHHX no^ BJIH^HHCM rano6apHHecKOH rHnoKCHH Ha
sxane npeHaxajibnoro pasBHXHH. CucxeMHbie HSMeneHHa ^anbi B
CB«3H C H3MCHeHH5IMH 6HOXHMHH H MOJlCKyjl^pHO-KJieXOHHOH
HeiipOHOB.
ABXOP .nnccepxauHH BnepBbie nonyHHJia 3KcnepHMeHxajibHbie ^oKasaxejibcxsa
H pa3JIHHHH B 34>4>eKTax ^eHCXBH^ HCKOMneHCHpyeMOH THno6apHHeCKOH
ranoKCHH (MCHee 5% KHCJiopo^a B ^bixaxejibHOH rasoBOH CMCCH) H
CHHxexHHecKoro rjHOKOKopxHKOH^Horo ropMona ^eKcaMexasona B
cpoKH npenaxajibHoro onxorenesa Kpbic.
BnepBbie npoBe^en SKcnepHMenxajibHbiH cpaBiraxejibHbiH aHaJiH3
ocoSeHHOcxeM HapyiuenHfl BHyxpHKjiexoHHbix MOjieKyjmpHbix H ropMonajibHbix
M6XaHH3MOB MO3ra KpbIC, BbBtlBaCMblX BO3AeHCXBHeM HCKOMneHCHpOBaHHOH
runoKCHH B nocJie^HeM TpHMecxpe GepeMCHHocxH HJIH BBe^eHHeM B xe )Ke cpoKH
3H#oreHHoro ropMoea - ^eKcaMexaaoHa.
nojiynenHBie ^aHHbie o6jra^aiox necoMHeHHOH HOBHSHOH. Pesyjitxaxti
3KcnepHMeHxajiBHtix pa6ox E. PL TKUIBKOBOH nojiHocxbio onySjiHKOBaHti B
oxeHecxBeHHbix H 3apy6e^cHbix peu,eH3HpyeMtix ns^aHHflx, neoAHOKpaxHO
^OKjia^biBajincb na Me^c^yHapoflHtix Kon^epeHUHax. B npeflcxaBjreHHOH pa6oxe
asxop o6o6maex pesyjitxaxti CBOHX HCCJie^oBaHHH H (jwpMyjrapyex co6cxBeHHtie
XpaKXOBKH H o6l.aCHeHHfl OCoSeHHOCXCH B3aHMOCBH3H CHCXCMHOrO H KJieXOHHOFO
ypOBHfl a^anxauHH Mosra K noBpe^c^aiomeMy rHnoKcnnecKOMy Bos^eHcxBHio na
npenaxajibHOM axane 4>opMHpOBaHHfl IJJIC.
TeopeTuqecKan H npaKTHHecKaa SHagnMocTb pa6oTbi COCXOHX B
3KcnepHMeHxajibHOM o6ocHOBaHHH conexaiomnxca a^anxHBHBix npoueccoB IJ[HC
MJieKoriHxaiomHX B OXBCX Ha ^03HpoBaHHyio HeKOMnencHpoBaHHyio rHnoKCHro,
npeaT>fl[BJTHeMyiO B nepHOfl «OXKpbIXHfl OKHa yH3BHMOCXH» npH 4>OpMHpOBaHHJI
HCHpOHHblX B3aHMO^eHCXBHH B nO3^H6M HpeHaxaJlbHOM nepHO^G pa3BHXHH
opranH3Ma. Sacjiyroii aBxopa HBJiaexcji nojiyneHHe H BsanMHoe yBH3biBaHHe
, xapaKxepH3yiomHx cHcxeMHbie, Me^KJiexonnbie, KJiexoHHbie H
MexaHH3Mbi pearnpoBaHHa na ranoKCHHecKoe Bos^eHcxBHe.
UCHHOCXL nojiynenHBix E.H.TrojibKOBOH peayjibxaxoB COCXOHX B
npOflCHCHHH 3HaHHMBIX acnCKXOB BHyXpHKJICXOHHOH CHFHaJlHSailHH B HCHpOHaX
npH HX CPOHHOM H oxcpo^CHHOM pearHpOBaHHH Ha rnnoKCHHecKyfO narpysKy.
3xo no3BOJiHX HaMexHXb nyxH paspa6oxKH HOBBIX cnoco6oB ^HarnocxHKH
npenaxajibHbix naxojrorHH. 3KcnepHMeHxajibHbie ^annbie coHCKaxejia 4)0PMHPyiOT
seKxop noHCKa 3(f)4)eKXHBHbix nyxen noBtiiiienHJi o6mew pesHCxenxHocxn
opraHH3Ma. HojiyHeHHwe pesyjibxaxti Moryx Gbixb Hcnojib3OBaHti npH cos^anHH
HOBoro noKOJieHHH ^apMaKOJiornnecKHx npenapaxoB, OKa3biBaiomHX
nanpasjieHHoe fleiicxBHe Ha KJiioHeBbie 3BeHb5i noBpe^^aiomnx MexaHH3Mos
csasaHHbix c rHnepaKTHBaaHCH myxaMaxeprHHecKOH CHrnajibHOH Tpanc^yKUHH
onocpe^yeMOH KajibuneBOH H (^OCC^OHHOSHTH^HOH cwcxeMaMH, a xaote c
napyiiieHHHMH HeHpo3H^OKpHHHoii peryjiaunH B opraHH3Me
QSocHOBaHHocTb H jocTOBepHOCTb nojio/KCHHH jHccepTauHH
KOJiHHecxBOM npOBe^eHHBix 3KcnepHMenxoB. ,U,HccepxaHi
KOMnjieKCHoe HsyneHHe flunaMMKH napaMexpos coMaxHHecKoro K
cencoMoxopHoro pasBHXnn Kpbic B panneM nocxnaxajibHOM OHXoreHese.
HCCJieAOBajia ^BHraxejibnoe, 3MoqHOHajri>Hoe, nccjie^oBaxejibCKoe noBe^eHHe K
cnoco6Hocxb K o6yHeHHK) sspocjibix ^cuBoxHbix. E.M.TiojibKOBa flonojiHHjra
onncaHHe CHCxeMHbix peaKuwii Ha rHHOKCHio conexaHHbiMH c HHMH H3MeH6HHJiMn
ropMOHajibHbix H BnyxpHKJiexoHHbix npoueccoB, ynacxBypomnx B MexaHH3Max
^opMHpOBaHHa peaKUHH Mosra npw BOS^CHCXEHH HeKOMnencHpOBaHHOH
riino6apHHecKOH rHHOKcun Ha pasjiHHHbix axanax npenaxajibHoro onxoreHesa
Kpbicw, a HMCHHO: HsyneHHe oco6eHHOcxH 4>yHKUHOHHpoBaHH« runnoxajiaMO-
rnno4)H3apHO a^penoKOpxHKajibHOH CHCTCMW, aKXHBHocxH BHyxpHKJiexoHHbix
CHPHaJIbKblX CHCX6M (KaJIbUHCBOH H <J)OC(j)OHHO3HXH,!JHOH), COOXHOIlieHHS HpO- H
aHXHOKCH^anxHbix CHCXCM B Mosre Kpbic Ha pa3Hbix cxa^H^x nocxnaxajibHoro
onxorenesa. Asxop ^HccepxauHOHHOH paGoxw nposejia cpaBHHxejibHoe HsyneHHe
^eKcaMexasoHa B npenaxajibHOM onxorenese B xe )Ke cpoKH na
OHHpOBaHHH HeHpO3H/IOKpHHHOH CHCXCMbl H aKXHBHOCXH
cHcxeMbi Mosra BSpocjibix Kpbic. B npeAcxaBJieHHOH pa6oxe
qupoBaHHaH cxaxHcxHHecKaa o6pa6oxKa MaxepHaJia. TCKCX
COCXOHX MS BBe^eHHH, o63Opa oxenecxBCHHOH H 3apy6e^CHOH
jiHxepaxypbi, onwcaHHa MaxepnajiOB H MCXOAOB HCCJie^OBaHHH, o6uiHpHoro
, nocBameHHoro onncaHHK) pesyjibxaxos 3KcnepHM6HxoB,
nojiyneHKbix pesyjibxaxos, saicniOHeHHH, BbiBOAOB H
jiHxepaxypbi, co^epxamero 101 oxenecxBenHbiH H 577 3apy6e^cHbix
Pa6oxa HJiJifocxpHpOBana mecxbioaecjixbK) naxbK) pncyHKaMH H
xa6jinu,aMH. Ylo MaxepnajiaM pa6oxbi ony6jiHKOBaHO 6ojiee 100 nayHHbix paSox,
33 cxaxbn B peuensHpyeivibix ^cypnajiax.
Bo Bse^eHHH y6e,zurrejibHO oGocHOBbiBaexca aicryajibHocxb TCMH, HCTKO
uejin H 3a^ann Hccjie/toBaHHa, a xaicace nojio^KeHH^, BbinocHMbie na
JlnxepaxypHtiH o6sop (rJiasa 1) CBH^exejibcxsyex 06 3py^HUHH aBTOpa. B
HCM paccMaxpusaioxcH KaK o6mHe acneKXbi a^anxaqHH Mosra MjieKonHxaromnx K
ranoKCHH, xaK n npoflBJieHna axux a^anxauHOHHbix npoueccoB Ha ypoBHe qejioro
OpraHHSMa, Me^CKJieXOHHblX BSaHMOACHCXBHH, KJiexOHHblX peaKUHH H ^HHaMHKH
BHyxpHKJiexoHHbix CHrnaJTbHbix MexaHH3MOB. Cjie^yex oxMexuxb
c6ajiaHCHpoBaHHoe no HOJIHOXC H XOHHOCXH onHcaHne anonxHHecKnx npoueccoe B
nespejioM Mosre (pas^eji 1.2.6).
3KcnepHMeHxajibHa» nacxb pa6oxw BbinojiHena Ha Kpbicax nopo^bi Wistar.
BospacxHOH ^HanasoH oxBaxbisaji npenaxajibHyK) 4>a3y (HaHHHaa c 11-x cyxoK
nocjie Hacxynjienna 6epeM6HHOcxH), nepHHaxajibHbiii nepHO^ n BKjuonaji 90-e
cyxKH nocjre poyKRQimx.
B pasflejie "OcnoBHbie Mexoflbi HCCJie^oBaHun" (rjiasa 2)
xapaKxepHCXHKa oSteKxa nccjie^oBaHHa n ^exajibHO onHCbiBaexcn
nacxb paGoTM. OpaBHJibHocxb Bbi6opa MCXO^OB Hccjie^OBanHa, HX
nocxaBJieHHbiM sa^anaM He Bbisbraaex COMHCHHK. Hcnojib30BaHHe innpOKoro
Mexo^H^ecKoro apcenajia no3BOJiHJia asxopy MHororpaHHo nccjie^oBaxb
AHHaMHKy (})H3HOJIOrHHeCKHX, 6HOXHMHHCCKHX H MOJICKyJIflpHO-GHOJlOrHHeCKHX
npoueccoB npHcnoco6:ieHHa oprannsMa ^HBOXHbix K AGHCXBHK) rHnoKcunecKoro
cxHMyjra.
K ^ocxoHHCXBaM 3XOH TjiaBbi oxHocHxca no^poSHoc H xopomo
HjiJiiocxpHpOBaHHoe onHcaHHe 6ojibiiiHHcxBa HcnojibsosanHbix asxopOM
3KCnepHMCHXaJTbHbIX
B o6uiHpHOH TpexbeM rjiasc AHCcepxaiiHH npHBo,u5ixcji co6cxBeHHbie
aBxopa. K&KAHH naparpacft .zioKyMeHXHpoBaH rpacJmnecKHM H
MaxepwajioM, HTO snaHHxejibHO o6.rcerHaex BocnpHHXHe H anajiH3
Ope}K,ae Bcero, E.H.TrojibKOBa H3Jio>KHJia pesyjibxaxbi
o6mecoMaxHHecKHx xapaKxepHCTHK H cencopHbix peaKUHH Kpwc B
nocxHaxajibHOM OHxorenese. ^Hccepxanx npoBO^HJia cpaBHeHHe
H3MCpeHHH, C^eJiaHHblX y HHTaKXHblX 3KHBOXHHX C ^aHHblMH, ITOJTyHeHHblMH Ha
KpblCKXaX, HbH MaxepH 3KCnOHHpOBajTHCb B THnOKCHHeCKHX yCJTOBHflX Ha 11-13-H,
14-16-H H 17-19-H ^HH nocjie nanajia GepeMennocxH. B Hxore OKasajiocb, HXO
rHno6apHnecKOH rHHOKCHH B nanajie, cepe^HHe H KOHUC xpexbeS
recxauHH npHBO^HJio K 3HaHHxejibHOMy 3aMe^jieHHio coMaxunecKoro
paSBHXHfl H 4)OpMHpOBaHHH CCHCOMOXOpHblX XapaKX6pHCXHK KpblCHX B
nocxnaxajibHOM nepHO/ie.
yxonneHHe rpannu «oKHa y»3BHMOCXH» E.H.TwnbKOBa npoBejia,
pe<})jieKxopHbie peaKUHH Kpbic B paMKax XOH ^ce sKcnepHMenxajibHOH
. OKasajiocb, HXO npenaxajibHaa rnnoKCHHecKa^ narpy3Ka no-pa3HOMy
na caMUOB H caMOK B xecxe Bbipa6oxKn H Bocnpon3BeAeHH5i ycJioBHo-
pe(J>jieKxopHOH peaKUHH naccHBHoro H36eraHH». OocjieAyioi
, HXO rnnoKCHa B npenaxajibHOM onxorenese HH^yunpoBajia
HapyuieHHH noBe^eHHK H cnoco6HocxH K o6yneHHK>. Y Kpbic,
Bos^eftcxBHio rHno6apHHecKoii rnnoKCHH na 14-16-e cyxKH
npenaxajibHoro onxorenesa, naGjiio^ajiocb noBbiuieHHe ypoBHa ^BHraxejibHOH
aKXHBHOCXH, BblflBJiaJIHCb HapymeHHfl (JDOpMHpOBaHHH ^OJirOBpeMCHHOH H pa6OHCH
Hapjmy c THnoKCHHecKOH narpysKOH asxop AHCcepxaijHH ncnojib3OBajra
3KcnepHMeHxajibHyio Mo^enb, B KOTOPOH pojib cxpeccopa BbinojiHHJio yBejiHHCHHe
B xKaHflx GepeMeHHbix caMOK KOHueHxpauHH ^eKcaMexasoHa (80 MF/KF) na 14-16 H
17-19 CyXKH reCXaUHH. V 3XHX ^CHBOXHblX, B OXJIHHHe OX KpbIC, HCHblXaBIUHX
FHnOKCHH, Ha6jIK)^ajIHCb OXKJIOHeHHS B 3MOUHOHaJIbHOM
H cnocoGnocxH K oGyneHHK) B cxpeccosbix cHxyauHJix. B HacxHocxH,
aeKcaMexasona na 14-16-e cyxKH B npenaxajibHOM nepwo^e paaBHXHJi
K yMeHbiueHHio, a BBefleHHe ^eKcaMexasona na 17-19-e cyTKH - K
ypOBHfl XpeBO^CHOCXH HpH XCCXHpOBaHHH CaMHOB B
Kpecxoo6pa3HOM JiaGnpHnxe. Bse^eHHe ^eKcaMexasona na 17-19-e
npeHaxajibHoro nepwo^a pa3BHxna Bbi3biBajro yBejraneHHe BpeivieHH
o6cxanoBOHHoro ycjioBHoro pe^jieKca y caMupB Kpbic, B xo^ce
^CKcaMexasona na 14-16-e cyxKH npHBO^HJio K napymeHHio
npouecca yrameHHa.
TaKHM oSpasoM, saBepuiHB Hccjie^oBaHHa BJIHHHHH runoKCHH H HHT.CKUHH
AeKcaMexasoHa B nos/jHeM npenaxajibHOM nepHo^e na cncxeMHbie npoueccbi E
opraHH3Me Kpbic^x, E.H.TrojibKOBa CMorna oxsexHXb, no KpaiiHeH Mepe
, na ^Ba sa^cnbix sonpoca. Bo-nepsbix, HS nojiyneHHbix MHHbix
, HXO «OKHO y^3BHMOcxH» B OXHOIUCHHH BJIH^HH^ THHOKCHH na
CHCxeMHbie npoueccbi B opraHHSMax HOBOpo^cAeHHbix MOJKCX 6bixb cy^ceno ^o 14-
16 cyxoK nepHo^a recxaqHH. Bo-Bxopbix, ^eficxBHe ^cKcaMexasona E
KOHueHxpauHH 80 Mr/Kr Ha GepeMCHHbix Kpbic ne aBJinexca nojiHbiM
rnnoKCHHecKOH narpysKH. VxoHHeHHe H £exajiH3auH5i 3XHX
BbiBo^oB GbiJiH npoH3Be/;eHbi B nocjie^yromHx GHOXHMHMCCKHX H
6HOJIOrHHeCKHX 3KCnepHM6HXaX.
H3BCCXHO, HXO fleHCXBHC CXpCCCOBblX ^aKXOpOB, X3KHX K3K rHHOKCHH HJIK
^eKcaMexasona, axxBHpyex rHnoxajraMO-rHno(^H3apHO-
CHCxeMy. YnacxHe SXOH cncxeMbi B peajiHsauwH cxpeccoBOH
peaKHHH onocpeziyexcK rjiiOKOKOpxHKOHAHbiMH ropMonaMH, Koxopbie
Bbipa6axbiBaK)TCfl Ha^noneHHHKaMH MaxepH, npoxoA^T nepes ruiaueHxy, H H3
nepH^epHHecKOH cncxeMbi njio^o-njiaueHxapHOH qHpKyji^aHH nerKo npoHHKaiox
B opraHHSM H cxpyKxypbi Mosra cospeBaromero opraHHSMa. Cxenenb BJiHJiHHa
HCKOMneHCHpoBaHHOH rHnoKCHH H fleKcaMexasoHa na (^yHKUHH rHnoxajiaMO-
rano(J)H3apHO-a,apeHOKOpxHKajibHOH cHcxeMbi y HOXOMKOB Kpbic,
B03£eHCXBHK) rHIIOKCHH H3 14-16- HJIH 17-19-e CyXKH 6epeM6HHOCTH XaOCC 6bIJia
Hccjie^osaHa B npe^cxaBJieHHOH pa6oTe. OKasajiocb, HTO npeHaxajibHbiH
THHOKCHHeCKHH CTpCCC HpHBO^HJl K IIOBbimeHHK) CTpCCCpeaKTHBHOCTH
rHnoxanaMO-rHno(})H3apHO a^peHOKopxHKajitHoM cucxeMbi. HapymeHHfl B ee
peryjiflijHH nponcxo^HJiH no npHHHHny oxpnuaxejibHOH o6paxnoH CBJTSH y caMOK
(HO ne y caMUos) Kpbic, nepe5KHBuiHX npenaTajibHyio rHnoKcmo na 17-19-e cyxKH
. Bbijin BbiHBJieHbi ^jiHxejibHbie Mo^H^HKauHH aKcnpeccHH TJIIOKO- H
peuenxopoB B ranriOKaMne H HeoKopxeKce B OXBCX Ha
ranoKCHio. BBe^eHHe ^eKcaMexasona na nocjie^HeH neAejie npenaxajibHoro
OHxorenesa xax^ce npHBO^HJio K Mo^H^HKaqHH aKxuBHocxw TJIPOKO- H
peuenxopOB, HO cxeneHb H HanpaBJieHHocxb
HapyuieHHH oxjinnaexcn ox BbisbisaeMbix
y^ajioct nposecxH HccjieAosaHHe
BHyxpHKJiexoHHbix peryjiHxopHbix CHCXCM B OXBCX na ^encxBHe H36paHHbix era
cxpeccopoB (rnnoKCHH H #eKcaMexa3OHa). y^anocb noKasaxb, HXO O^HHM H3
nOCJieACXBHH HX ^eHCXBHa HBJiaiOXCa CXOHKHe MO/tH^HKaiZHH 4)OC(^OHH03HXH^HOH
CHCTCMbl, KOXOpaa, K3K H3B6CXHO, KOHXpOJTHpyeX MCXa6ojIH3M H <{)yHKUHOHaJIbHyK)
aKXHBHOCXb HCpBHblX KJTCXOK, B XOM HHCJ16 HpOJIH^epaUHK), pOCX,
nporpaMMHpyeMyio ruGejib, CHHanxHHecKypo nepe^any CHrnajioB.
B CB#3H c o6napy^ceHHbiMH panee HapymeHHHMH cnocoGnocxH K
oSyneHHio Ba^cHo 6biJio oco6oe BHHMaHHe y^ejinxb COCXOHHHIO
(J)oc4)OHHO3HXH^HOH CHCxeMbi He xojibKo B HeoKopxeKce, HO H B rannoKaMiie
Kpbic, nepe^cHBuiHx npenaxajibHyK) THHOKCHIO. 3KcnepHMeHXbi noKasajiH, HXO
rnnoKCH^ B npeHaxanbHOM nepnoAe HHAyuwpyex AJiHxejibHbie H3MeneHHfl
aKXHBHOCXH 4)OC4)OHHO3HTHAHOH BHyXpHKJieXOHHOH peryJTHXOpHOH CHCXCMbl
Mosra Kpbic, HXO npo^BJiaexcH noBbimeHHeM ypoBH^ co^ep^caHH^ KJiioHeBoro
KOMnOHCHXa (J)OC({)OHH03HXHAHOH CHCX6MbI - 4)OC(j)aXH/IHJIHHO3HXOJia-4,5-
AH(})oc(J)axoB B THimoKaMne H HeoKopxeKce 14-cyxonnbix Kpbic. npHHeM y DJIOAOB,
FHIIOKCHH Ha 14-16-e cyxKH npenaxaJibHoro OHXorenesa, 3XH
H3M6HeHHH COXpaHJUIHCb H BO B3pOCJIOM COCXO5IHHH.
McCJie^OBaHHH peaKUHH (J)OC(J)OHHO3HTH4HOH BHyXpHKJieXOHHOH
peryjiflTopHofi CHCxeMbi npOBO^HJincb xaiOKe H B Henponax nepejKHBaiomHx
cpeaoB o6oHHxejibHoM Kopbi MO3ra. OxMeneno snaHHTejibHoe yBCJiHHeHHe
aMnjiHTy^bi 4>oc(})OHHO3HTH^Horo oTBexa na ^eHCTBue rjiyraMaxa B cpesax MO3ra
14-CyTOHHbIX KpblCHT. HpH 3TOM (^OCO(j)HHO3HTHAHbIH OTBCT Ha
rjiyxaMaxa o6HapyKHBaeTca H y sspocjibix >KHBOTHbix, nepeneciuHX
na 14-16-e cyxKH (HO ne na 17-19-e) recxauHH. Hapa^y c SXHM
auHfl 3KcnpeccHH HHO3HxojixpH(})oc4)axHoro peuenxopnoro
KOMnjieKca B rHnnoKaMne Kpbic.
Bse^eHHe .ueKcaMexasona na 14-16-e H 17-19-e cyxKH npeHaxajibHoro
OHxorenesa xaK^ce 3HaHHxejibHo noBbiinajro ypoBenb co^ep^caHHH
nOJIH^OC(J)OHHO3HXHflOB B THnnOKaMne H HCOKOpXeKCe B3pOCJlbIX KpbIC H
3KcnpeccHio HHO3HxojTXpH4>oc(})axHoro peuenxopHoro KOMnjieKca B rannoKaMne.
Tax Kan npenaxajibHan runoKCHa, nepeneceHHaii KpbicaMH B nocjie^HHi!
XpHMCCXp GepeMCHHOCXH, npHBO^HJia K Bblpa^KCHHblM H3MeH6HH5IM aKXHBHOCXH
BHyxpuKjiexoHHOH curHanbHOH xpancziyKaHH, onocpeziyeMOH ^OC^OHHOSHXH^HOH
CHCXCMOH, xo E.H.TiojibKOBa npeAnoJio^cHJia, HXO rjiyxaMax Bbi3biBaiomHH
THApOJIH3 nOJIH(J>OC({)OHHO3HXH,ZIOB B KJICXKaX MO3Pa B
Mexa6oxponHbix rjiyxaMaxHbix peqenxopOB I rpynnbi (ImGluR),
aKXHBHOcxb KOTOpbix ^opMHpycxca B npeHaxanbHOM nepHo^e, MO^cex BOBjienb 3XH
peuenxopbi B <j)OpMHpoBaHne H/HJIH nocxnaxairbHoe no^^ep>KaHHe napyineHHH,
Bbi3biBaeMbix npenaxajibHoS THnoKCHeH. Bbijro npoBe^eno H3yneHHe
nocjie^cxBHH BJiH^HHa npeHaxajibHOM ranoKCHH na 4>yHKUHOHajibHoe COCXOSHHC
nOJ!H(J)Oc4>OHHO3HXH^HOH H KajlbUHCBOH peryJT^XOpHblX CHCXCM KpbIC ^ByX
B03pacxHbix rpynn, nyxeM OUCHKH KajibuneBOH CHrnajiHsauHH, onocpe^yeMOH
B036y^<^eHneM ImGluR peqenxopos B nepe>KHBaK>mHx cpesax oGonnxejibHOH
Kopbi MO3ra. .Una cxHMyji^UHH MexaGoxponHbix rjiyxaMaxHbix peuenxopoB nepBOH
10
rpynnbl (ImGluRs) npHMenjuiH napnyio annjiHKan,Hio necejieKXHBHoro aromicxa
S(3-5)-^HrHZtpOKCH-(})eHHJirjTHUHHa B KOHCHHOH KonneHxpauHn 100 MKM B
xeneHHH 2 MHH. TaK KBK HanGojiee snanHMbie HSMenenHJi aKXHBHocxn
<j)occ[)OHHO3HXH,z],HOH cHCTCMbi 6buin paHee o6Hapy>KeHbi y Kpbic, nepeneciuHx
ranoKCHio na 14-16-e cyxKH recxanHH, HccjieAOBaHHK aKXHBauHH Mexa6oxponHbix
rjiyxaMaxHbix peuenxopoB 6biJio npoBe^eno na xpbicax HMCHHO axoM rpynnti.
Pesyjibxaxbi Hccjie^oBaHHH noKasann, HXO runoKCHa, npe^'biiBjuieMaa KpbicaM
na 14-16e cyxKH npenaxajibHoro OHTorenesa, Bbi3biBajia oxcponeHHbie H3MeneHHa
aKXHBHOcxn rjiyxaiuaxeprHHecKOH CHrnajibHon xpancflyKUHH, onocpeflyeMOH
Mexa6oxponHbiMH rjryxaMaxHbiMH peuenxopaMH B Hefiponax nepejKHBaiomHx
cpe3OB Mosra, a xaiotce ypoBHCM co^ep^aHHfl BHyxpHKJiexoHHoro KajibUHa, KEK y
lOBCHMJIbHtlX, XaK H y B3pOCJlbIX 5KHBOXHBIX.
CoHCKaxejieM xaK^ce GLIJIH BbinojineHbi nccJie^OBaHHa no onpe^ejieHPiio
aKXHBHOcxn npou,eccoB nepeKHCHOro OKHCJieHHa JTHHHAOB MerviGpan KJICXOK Mosra
no^onbixHBix ^HBoxHbix. O cxeneHH HSMeneHHfl npoueccoB nepeKucnoro
OKHCJICHHH CyflHJIH HO CO^epK3HHK) B XKaHflX MO3Fa /nieHOBHX H XpHCHOBblX
KOHi>K)raHxoB (npo^yKxoB, pearapyiomHx c 2-xHo6ap6HxypOBOH KHCJIOXOH) H
OCHOB3HHH LLlH^^3- CxeHCHb OKHCJICHHOCXH MCM6paH OUeHHBaJlH HO
KO3$(^Hu;HeHxy KjieHHa. HsMenenHa ypOBHefi KOMnonenxoB CHCXCMH
nepeKHCHOro OKHCJienHa JIKHHAOB (IIOJI) onpe^eJiJiJTH B Kope H rannoicaMne y
Kpbic cjie^yioinHX rpynn: 1) y HHxajcxnbix 14-cyxoMHbix H B3pocjibix caMiJiOB Kpbic;
2) y 14-cyxoHHbix caMuos Kptic, noaBepraBuiHxca BO3^eHCXBHio xa^cejion
rnnoKCHH Ha 14-16-e H 17-19-e cyxKH npenaxajibHoro pasBHxna.
BbiJio npoBe^eno cpaBneHHe Me^c^y ypOBH^MH HHxencHBHocxH npoueccoB FTOJl y
HHXaKXHblX 14-XH H 90-CyXOHHbIX KpblC.
OKasaJiocb, HXO nmoKCHa, npe^taBjiKeMaji Ha 14-16-e cyxKH (HO He Ha 17-19-
e) npenaxajibHoro onxorenesa, HHAyanpyex Bbipa^cennyio ^jiHxejibHyio
npoqeccoB nepeKHcnoro OKHCJieHHa jiHnn^oB B rnnnoKaMne H
11
HeoKopxexce Kpbic na <J>oHe cHHxceHHji 3KcnpeccnH nenxH^Hbix
(xHOpe^OKCHHa-1, THOpeAOKCHHa-2 H cynepOKCH^aHCMyxas)
H, naKOHeu, B noribixice cyMMaxHBHO oueHHxb B3aHMO£eHcxBHe
ranoKCHHecKOH narpysKH na Gananc npoueccoB HeHporenesa H
HeHpo£ereHepau,HH B passHBaromeMca Mosre, E.HTioJibKOBa wccjieAOBajia
HHXeHCHBHOCXb anOHXHHeCKHX HCXO^OB y3M6pHOHOB, K)BeHHJlbHbIX H B3pOCJlbIX
>KHBOTHbix, B paMKax CBOCH 3KcnepHMeHxajibHOH Mo^ejiH. HojiyHeKHbie ^aHHbie
CBH^exejibcxByrox B nojibsy rnnoxesbi o cMemeHHH Gajianca Me^c^y HeHporenesoM
H HeHpoAereHepaqneH na npeHaxanbHOM H nepHHaxaJIbHOM sxanax.
THKHM o6paaoM, na ocnoBaHHH MHoroHHCJienHbix ^annbix, nojiynenHbix B
HCCJte^OBaHH^X CHCTCMHblX H KJICXOHHblX peaKUHH MJieKORHXaiOLUHX Ha
npeHaxajibHbie runoKCHHecKHe Boa^eHCXBHH H
E.H.TiojibKOBa cMorjia yGe^nxejibHo o6ocHOBaxb
1. rnno6apHHecKaa THHOKCHJI (5% KHcuopoAa B xeneHHe 3-x
xpexKpaxHO c HHxepBanoM 24 naca), npe^-baBJiaeMafl caMKaM Kpwc
Wistar B xpexbCM xpuMecxpe 6epeMeHHocxH oKa3bmaex neraxHBHoe
BJIH^HHC Ha pa3BHXH6 nOXOMCXBa.
2. «OKHO y«3BHMOcxH» B xo^e BJTH^HHH rnnoKCHH na pasBHXHe Mosra HJIOAOB
onpe^ejiHexca HnxencHBHocxbio npoueccos neiipo- H rjinorenesa H
yCXaHOBJICHHa CBH3CH MOKfly KJICXKaMH MOSra. B IIIHpOKOM CMblCJie 3X0
OKHO npHXO^HXC^ H3 XpeXHH XpHMCCXp GepCMCHHOCXH KpblC. B y3KOM
CMbicjre 3x0 14-16 ^HH nepHOfla recxaqHH.
3. fleHCTBHe H36paHHOH flO3bI CHHXeXHMeCKOFO rJIIOKOKOpXHKOHAa
(80 MP/KF) ne flBjraexca nojiHbiM anajioroM
aBxopoM BapHanxa rnnoKCHH. O^naKo
fleKcaiviexa3OHa MOKHO paccMaxpHBaxb KaK SBCHO naxojiorHHecKoro
npouecca, onpe^ejiaeMoro XH^CCJIOH cxeneHbro
B opeHaxajibHOM
4. O6uiHpHbie HccJie^oBanHfl asxopa nosBOJiHJiH o6napy>KHXb
KoppeJiflUHH Me^Kfly peaKUHHMH opraHH3Ma MJieKonHxaiouiHx H;
npenaxajibHyio ranoKCHK) Ha cncxeMHOM H KJiexoHHbix ypoBHflx.
B Kanecxse He,aocxaxKOB, CBHsannbix oneBH^HO c H3jio^ceHneM pesyjibxaxoi
oBe^e'HHbix HccjieflOBannH, cjieziyex Haasaxb oxcyxcxBHe B xexcxe ^Hccepxaqm
o6ocHOBbiBaiomHx napaMexpbi rnnoKCHHecKoM narpy3KH, HcnojibsyeMOi
AHccepxanxoM na npoxa^eHUH BCCH 3KcnepHMeHxaJibHOH pa6oxbi. Hnane roBopa
KaKOH 4>opMax npeffbXBjiQHiw. rHnoKCHHecKoro cxHMyjia HawGojiee
K3K HCCJie^OBaxeJlbCKHH HHCXpyMCHX.
B xeKcxe ^HCcepxauHH xaK)Ke oxcyxcxsyex oGocnoBaHHe
Bbi6opKH penpeseHxaxHBHbix MapKepoB Bpe^onocHoro ^eHCXBH^ npenaxajibHOP
rnnoKCHH B paMKax nccjieAOBaHHOH SKcnepHMenxajibHOH MO^CJIH.
saMenaHHH ne yMajiKiox 3HaMeHH« npo^ejiaHHOH aBxopoiv
H 3KcnepHMeHxaJii>HOH pa6oxbi.
HXOFH, cjie^yex oxMexnxb Kyjibxypy (j)H3HOJiorHHecKoro K
6HOXHMHHecKoro MbiinjieHHK aBxopa, jiorHHecKyFo csa3b oxAejibHbix nacxeK
Z^HCcepxa^HH, HCHOC HSJio^ceHHe pesyjibxaxoB.
c^ejiaHHBie aBxopOM ^ocxosepHbi, cooxBexcxByiox
pesyjibxaxaM H He Bbisbmaiox COMHCHHH.
ABxope^epax nojinocxbio oxpa^caex co^epacaHHe AnccepxauHH.
fljig BHejpeHHH B npaKTHKv. Pesyjibxaxbi £HccepxaunoHHorc
E.H. TioJibKOBOH Moryx 6wxb Hcno;ib3OBaHbi npw nxeHHH KypcoE
JICKUHH AM Bpaneii, cneuHajiHSHpyiomHXCJi no aBHauHOHHOH, KOCMHHCCKOH H
BOflOJiasHOH Me^HUHHe, a xaK^e na jieKqHHx no rnneKOJiorHH
HHCXHxyxoB. MaxepHajibi ^nccepxauHH cjie^yex peKOMeH^osaxb
HcnojibsoBaHHH npH HXCHHH KypcoB jieKitnw H npoBeAeHHH npaKXHHecKHx
HO oGmCH (J)H3HOJlOrHH, BOSpaCXHOH (J)H3HOJIOrHH, 4)H3HO-riorHH
CHCXCM H (J)H3HOJIOrHH £bIXaHHJI H3 Ka^e^paX HOpMaJIbHOH (J)H3HOJTOrHH
Pesyjibxaxbi .aHccepxaHHOHHOH pa6oTbi Moryx 6bixb nojro^eHbi B ocHosy
npHKJia#Hbix nccjie^OBaHHH no BbiGopy cpe/icxB KoppeKiiHH
Mosra nejioBeKa, ycHJieHHH ero pesHcxeHTHOCTH K ACHCTBHK)
SHHSOAOB npeHaxajibHOH rwnoKCHH. Maxepnajibi ^aHHoro
cnoco6Hbi cxaxb OCHOBOH ^Jia paspaSoxKH peKOMen^auHH no
xaKXHKe MoGnjiHsauHH 4)yHKUHOHajlbHMX pesepBOB <{)H3HOJiorHHecKHX CHCXCM
opraHHSMa na axane pea6HJTHxai;HH Hosopo^K^eHHbix nocjre ocjioxneHKbix po#OB.
^Hccepxanxa HBJT^IOXCH neo6xo^HMbiM
bix Haynnbix FIOHCKOB B oGjiacxn
MexaHHSMOB a,aanxauHH Mosra K ^CHCXBHIO 3KcxpeMajibHbix (J>aKxopoB
BHyxpeHHeH H BHeuiHen cpe^bi.
3aKJiH)HeHHe. flnccepxauHfl E.H. TiojibKOBOH npeACTaBjiaex co6oii saKOHneHHyio
Haynnyio pa6oxy, o6o6maiomyK) 6ojibinoe HHCJIO, nojiyneHHbix asxopoM HOBbix
4)axxoB. Ee MO^CHO KBajiH^HUHposaxb, KaK HOBOC Kpynnoe AOCXH^ceHHe B
4)H3HOJIOrHH LJHC H, B H3CXHOCXH, B oGjiaCXH 4>H3HOJlOrHH paSBHXHH
HepBHOH CHCXCMbl HCJlOBCKa H ^CHBOXHblX.
^HCcepxauHOHHa^ pa6oxa E.M. TiojibKOBOH «MexaHH3Mbi
naxoJiorHHecKHX COCXOHHHH Mosra B OXBCX na Bos^eMcxBHe rnnoKCHH B
npenaxajibHOM oHxoreHese», HBJIHCXCH nayHHOH KBanH^HKauHOHHOH paGoxofi, B
KOXOpOH, Ha OCHOBC npOBe^6HHbIX aBXOpOM J1HHHO HayHHblX HCCJie^OBaHHH
ocymecxB^eno pemenne aKxyaJibHbix sa^an, HMeiomnx Ba)KHoe snaneHHe ^Ji»
HOBWX i^HSHOJiorHHecKHx MexaHHSMOB ynpaBJieHH5i npoijeccoM
opraHHSMa B uejiOM H LJHC B nacxHOCXH K ^CHCXBHIO
ranoKCHnecKHX narpysoK na paHHHx 3xanax
paSBHXHH. Ho COBOKynHOCXH HOBHSHbl HCCJie^OBaHHfl, AOCXOBCpHOCXH
nojiyneHHbix pesyjibxaxoB, HaynnoH H npaKXHHecKOH
14
Ha
, pa6oxa cooxBexcxByex xpe6oBaHH5iM n.9
o npHcy>K,fl,eHHH ynenbix cxeneneH» (nocxaHOBJienHe
PO ox 24 cenxaGpa 2013 r., jsr«842), npeAT>^BJiHeMbiM K
coHCKanne yneHOH cxeneHH ^OKXopa GnojiorHHecKHX nayx no
03.03.01 - (fmsHOJiorHji H Mo^cex 6i>ixb npe^cxaBJiena K ny6jiHHHon saii^Hxe B
flHCcepxainioHHOM cosexe, a caM asxop, HSBecxHbiH cneunajiHcx B o6nacxH
HeHpo(^H3HOJiornn, sacjiy^cHBaex npHcyac^eHH^ HCKOMOH cxeneHH.
npo4>eccop Ka^e^pbi xoKCHKonorHH,
3KCXpeMaJIbHOH H BO^OJiaSHOH
FBOY BOO C3rMy HM. H.H. MeHHHKOBa
MnnsApaBa POCCHH
A. 6. H. A.H. Bexom
06 asTppe ox3biBa;
Bexoui
Mpec: 191015 CI16, yn. KHponnafl, j\A\. +7-91 1-901-37-12, E-mail: [email protected]
