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1. 3ATAJIbIIA IHOOPMAIIIS NPO NPO€KT

Tpuea,rict, rr.ronauu-r llpoerrytIo\nor - 27 .10.20203axiuqeuuq - 31 .12.2021

3ara,rrua naprict, llpoenry, rpn. 9 050 000"0

Bapricrr flpoerry ro poKix, fpn.:1-fi pir 310Q0-l00Q,lL2-ft pir O05OQ0O0

IHOOPMAIITfl TIPO BI4KOHABIIIB IIPO€KTY

4o u.rxonanru llpoexry 6y4e :a;ryreuo 5 nuronanqin, : nrlx:

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innri npauinriar<u 2.

1. pEu,4l{q A.B., Incrraryr rrlonexylrpHoi 6ioaorii i reuerrmu HAH Vr<parnz, sar. ni44iny, g.6.u.,

npo$ecop, qneH-KopecnoHAeur HAH Yrpaiuu

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Kponr.rnro C.B. Incrr,rryr lronetcy:r.apuoi 6ionorii i renerrar<u HAH Yrpainv, x.6.u., c.n.c.

fp.asuona T.A., Iucr:zryr MoreKyirspHoi 6ionorii i renernr<n HAH Yxpaiuu, K.6.rr., c.H.c.

flanrriecrxr.rfi C.B., Incrraryr rrroneryn-rpnoi 6ionorii i renerurcu FIAH Yrpaihlt, Ira.n.c.

fy6epnaropoea A.O., Incrurl'r uo:rery:rrpnoi 6ionorii i renerurr,r HAH Vrparhu, acnipanr.

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4. OilUCIIPO€KTy

TA OPIAIII3AIIIrcG)

4.1. Mera IlpoercryBugnaqenns po:ri TKS4, iioro iso$opnu TKS4b ra nepnporinir WIP i CR16 y rpopr,ay'nauni

nporeinonux rollnrercie niA qac euAouuro3y ra crlrHilnBHlrx npoqecio, ulo BrIJIIrBullorb Ha yrBopeHHtinearonoaift.

4.2. OcnosHi 3aBAaHHs llpoeicryBzsHa.regus nowrx naprnepin WIP, CR16, TKS4 ra TKS4b, ulo 6epyr6 f{acrb y enAorlarosi ra

u.rruanuifi rpanc,ryxqii Ta npoaHaJri3yBarq BnrrllB nocr-rpaacnrqifinrx rr.ro4uq[ir<aqifi na sutsreHissaer\aoAii. ,4ocniAurlr uoN:runicru noKanisaqii TKS4b ra CR16 e insaaonoaitx. flpoana,riryearr-rpieui excnpecii reHie TKS4. TKS4b. WIP ra CRl6 B n),xnHHZIX rpyAHoi 3tulo3lr JIloAfi lu4. pisuux racryrreueM arpecrlenocri i ueracra:1nannx.

4.3. ,{era.nr,uui i : ru icr f lpoenry:

- Cywacuuft cran npo6:relruOAuuuu i: rnroqoeux xoNrnonenris iusaAonoaifi paxoBr4x rrtiruu e nepnpodn WIP T a aganrep

TKS4. Xoqa qi nporeinra acouiiionani is rreracraryraunnr rnirrEu paxy rpy4Iroi :a,roaz, ixHresaer\,roAis is nporeinalrz eHAorlaTo3y, Be3uKyrspHofo lprucnopry Ta cr,rfHarlbHlrx (acr<aain xirirranz exonrercri iusa3nnHux npoqecie He BLIBqeHa, ocxi:rsxz ponr ieorpopuz TKS4b ra nepnporiHa CRl6 y

$opvysauui iHeaAono4ift aoci He eusqanact.

- Hosr4sHa llpoexryB xoqi peanisaqii npoercry nnepure 6yqe AocniAxeno excnpecirc xolntnoHenris iusaAoloAifi

TKS4, TKS4b, WIP ra CRl6 B []xrr.rHax rpyrHoi 3aro3r,r nroar,rHrr, pi:r*rx ra cr]rneHeM arpecnenocrii rnreracra:1'nanru. Pesy:n raru [poeKTy Ao3Bontr6 3gar{Ho po3llupmz eiAolallfi iureparrolr(JtroqoBr{x nporeiuin innaAonoAifi i eussprtu ixnifi gs'sgoK i: nporeinauu eHAoIILITo3y ra cI4rHiIrIbHIrxracragin, Bax;rr{Br4x AJII innasii x,rirrlu.

- MeroAo:roris aocriAxeuqsErcnpeciro reuin y 3pa3K{tx ny<ruu ana,ris)iBaruMyrr, 3a AonoMororc rinrricnoi flJIP.

Yrnopennr nporeihonux KoN.rurercis in vitro nepenipnuruyru npequuiraqiero GST-saurux nporeihir

ra xoiul'nonpequnirarliero, a ix :rora;ri:aqiro s Knirtzrri - (fnyopecqenrnolo MiKpocKolierc. PoJIb

Aocri.{xysauux nporeiuin s iHna3ii ana:risynaruruyrr na Mo.4eJIbI{Lrx rnitunnnx :riuir,

uoAudironannx 3a AoroMorolo rexHororift Flp-In ra CRISPR/Cas9.

OTPI4MAHI HAYKOBI AEO HA}'KOBO-TEXHIIIHI PE3YJIbTATI{:

Ocxinrxlr Meroro nepmoro eraly HaIIIofo rrpoeKTy 6yro numnennr HoBr]rx nporeihonnxnapnepin ,qnq TKS4, TKS4b, WIP ra CR16, cnepuy 6y;ro ueo6xigno orprrMarrr ni,qnoninniperou6iuaurui rporeiHu, 3oKpeMa SH3-aorrresu nporeiuin AMPHI, BIN1, GRB2, NCK1, NCK2,CRK, CSK, PLCy1, SRC ra SRCn, qKi norenrlifiHo Mo)rq/rb B3aeMoaiqm is nponiHonuura Morr{BaMu4ocni4rrynaur.rx nporeinin po4uun TKS ra eepnponinin. V nerrop pGEX4T3 6yno r.nononauo x,{HKSH3-.qoueriin ITSNI, ITSN2, CTTN, AMPHI, BINI, NCK, CRK, CSK, PLCTI i SRC, a raroNn6yAonarro KoAyroqy noenoposuipny noc:riAoeHicrb a,qanrepnoro nporeiuy GRB2. Taxox y BeKropripcDNA4/His Ma.rA, pCMV-2HA ra pCMV-myc 6yrra rnonona"ui nocai4onuocri GRB2, WIP, CR16ra TKS4b. Orpurnrani pexou6inanrni nrasui4ri roucrpyxqii 6y:ru nuropucraui 4rrr er<cnpeciiperonr6inanrnux nporeiuia n 6arcrepirx ra uirruax mo4rzulr nisi\ 293.

Buropucronyrovr4 MeroA npequniraqii GST-srurrx 6imin in vitro,6ytro igeurra$irona.no uonuxnaprnepin pery:rmopin no:rinepusaqii arrlury WIP i CR16 ra Arrr a,4anrepnoro nporeihy TKS4.3oxperua. uaurl iaeul.rSiKosauo llicrr, noerx nporeinonux naprnepie WIP cepea pirrrux

Symqioua;rruux rpyn, a caMe: eH.4our4To:nrrx nporeinin AMPH1 i BIN1 ra nporeinin cr4rHarrbHr'rxxacKatie xlirnuu CRK. PLC1l. CRB2, SRC. Orprrlraui gaui noxyrs BKa3yBar4 Ha re. u1o uiesaeN,roAii peanisyerrca s iHea"qonoairx, ocxi.nrr<u WIP e oauurra 3 K;rroqoBvx xounonenriu quxcrpyroyp. B noaa,rruouy nnaHycrbcr nepenipuu ssacN4oairo qrx nporeihie in vivo rtnqxotv,roivyuonperln n irauii ra neperipuru ix roloranirauiro y r;tinrHax aAeHoKapqr.rHoMr.r rpyruoi 3ano3nNrcAIIHII.

Taxox 6y:ro BmBJreHo siciru{ Honux naprnepie ar<run-se'xsy'ralnnoro nporeina CR16 cepe4pi:nux $yrmuioHarrrHrrx rpyn, a caMe - AMPH1, BINI, CTTN, CRK, PLC1l, NCK1, NCK2, GRB2ra SRC. Orpurr.raui peynbrarr.r Moxyr6 cai4vuTu npo norenqifiuy )nracr6 CR16 y Knarplrn-onocepeaKoBaHouy erg,ounTori ra pisHovaHirrlrx carHzIJrbHhx uurflxaxa rc.nirrmn- 3oKpeMa BKacKaAax, rlo orrocepelroBylorrct $oclfoinosuro:rt[oc$atarru ra rupo:uurina:arrlr, ro4i xn6esnocepe4n-a po:t CR16 y $opuynanni innanonoaifi 6yAe onnuarucr Ha HacrytrHl,rx erarltx npoeKry.

Ha:un 6yrio Br4rBJreHo raxoN niciu nonux naprnepiB a,qaflTepuoro nporeiha TKS4. 3or<perua,*aeuo4i,a rrora3aHa anr TKS4 i aAanrepsux 6i:rKis NCKI, NCK2, GRB2 ra CRK, riua:u SRC,

Soc$o:rinaru PLCy1, i eH,uouuro3Hr{x nporeihir AMPHI ra BIN, nrca:yoqll Ha re, IrIo ,4oc:riAx}naninporeiHu Moxyrr, Sopvyeara KoMnJIeKcI,I e iuearonoAitx pzlxoBrrx r,rirus. trto 6yaenilraepgNyearucr, Ha HacrynHllx eralax rpoelcy. Hapasi nsaeuo4iro uix TKS4 ra GRB2 6y,:ronigrnep4xeno in vito tcoivryuonpequniraqiero rporeinorrx r<oMnnercis i: nigaris rniruu rpyanoi3aJro3r,r a{eHoKapqenonu MDA-MB-23I, rc 6y:ro uagexcnpeconauo per<on6inanrnlrfi nporeih Omni-GRB2. Tanox 6yno nepenipeno (bopMyBauut KoMrlneKcy TKS4-GRB2 npu arcrznaqii )'rBopeHIUIiuna:usu[x crpyKTyp y Krir[Hax. Pineur sn'rs1'raHH{ nporeiuiB rre 3pocra€ npu crrarrayn-rqii r,riruntfop6o,rosnv e$ipor.,r - einorr4nv iHlyxropola )'TBopeHHt iHsaaonoaift. BKa3)'rcwr Ha re. Ilo ngacuoaisuiN TKS4 ra GRB2 y minrnax MDA-MB-231 rrloxe 6ym KoHcrLIryrHBHoIo i seo6xianoro A:rqt|yrruioHysaunr uux paxoenx xrirr,tu.

B xo4i aHa:risy ssaeNaoaifi iao(fopun TKS4b nonux uaprnepin ne 6yro BrrrBrleuo. 3orpeua,6yno ncranonneno, rqo TKS4b ue nsaeuogie is SH3-.qoNaeHaMr.r nporeinin eHAorlr{To3y (AMPHI,BINI, ITSNI, ITSN2) ra cr{ruzlrlrrt4x nporeiHiB (CRK, GRB2, SRC, PLC 1l), ma:yto'tu uaNroN,'rr4sicrr icuyeanru irer<auoui'mzx $ynr<qift qiei i:o(fopuu y x-niT uni.

Anl AocriANeHnr Oynr<qift iso(fopuu TKS4b ra ii' nsaeNroaifi 3 nporeiHaMl{ fiaprHepztMlr 3a

AonoMororc Flp-In rexnonorii 6yno crBopeHo xniruuuy niniro T-REx-293 a perynronanorocra6ilrsoro na4ercupeciero qr,oro nporei'ua, xra iu,41'r<yeruc.f, arru6iorurolra 4or<cnqrlrc'linolr.Erccnpeciro qroro pexou6inaHrHoro flporeiHa 6yao nigrnep4xeHo 3a AonoMororc Becrepn-6:rorar-ra,riry. Ha Hacr)mHHX eranix nocniaxeHHt crBopeHa nto4ers 6yge Bl'rKopxcraHa .4rc AocaiaNeHHcnnnuny TKS4b na $opultauua insa,qonoAiii ra Mirpauiro r.nirun.

Pesylrraru npoeKTy 6yA1'rr rrar<opucraxi Anr crBopeHns Monel(yJrlpHo-Aiarnocruqnuxragenefi na ocHoei HoBrrx nporuocrrr.nrnx ifar<ropin (WIP, CR16, TKS4 ra TKS4b) 4:rr ruracu$ixaqiira gr.r$epenqiaqii pary rpy4noi 3ano3r4 3a piBHeM iuBa3l4Buocri ra Meracra3yBaHHs. I{e 4oseo:rurrcrBopt4Trr uony a6o BAocKonaJrrirrr eNe icuyro.{i Tecr-crrcreMr4, 3a AonoMorolo IKI,IX Moxua 6yAero.rHirxe fiporHo3)'Barn Br.rHrrKHeHHff .4t4 crilJrbH r{x N,reracrasin ra peur,r,ryrnin [yxnl4H rpyaHoi sanorn.

Kpirr.r roro, pe3yJr6Tar[r 4ocri4xenux MoJreKyJrrpnrrx MexaHfuMiB iHBa3muocri anoxricurx xnirr.rn,uon'gganrx is $y'nruionyrannm.r nporeinin WIP, CR16, TKS4 ra TKS4b, Moxyrr 6yrur nuropucrarriaJrr rroAaJrbmoro crpuniury nonux norerqifurrx uimeueft xirrriorepauenrnwlra< areurin,cnptMoBau[x na inri6lnarru-r inra4onogift. Crnopenna cnequ(fi'nrrn inri6iropin aJUr yrBopenruringagr.rsHux crpyKlyp Ao3BoJrrrT6 3Htr3r4TI{ rr.reracrarnwrnfi norenqian 3JroEdcr ry xnirr,rn. Tar<rnraqI{HoM, orpurraani pe3ynbTar{ Moxyrb 6yru nuropucrani y 0ynaarrlenramno-nayr<onift,ra6oparopnifi, rniuisuift ra (fapuaqerrrwri nparuqi AJrr HayKoBrx 4ocligxenl, ,4iarsocrrrr.r ranixynanu.r :roxricnrx nyxrrr4H rpyAuoi ra.norn, rp]uryroucE Ha MoJreryJrrpuux rraexasi:lrax(f opqeanlrr iusaAonoAifi .

Hayronufi rcepinunn rlpoexry

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