ABSTRACT
JLHV LHV OLFDWLRQV LRQV WWHUQ5HFRJQLWLRQ ELQDWLRQD3HUVSHFWLYH
INTRODUCTION
JH IDFLQJ WR[LFRORJLVWV WRGD\ LV WKH GHYHORSPHQW RI QHZ HQWLÀFDWLRQDQGFKDUDFWHUL]DWLRQRISRWHQWLDOKHDOWKRU HQYL UDFWLFDOWR[LFRORJLVWVKDYHDYDLODEOHQXPHURXVLQYLWURDQGLQ LQHWKHSRWHQWLDORIFKHPLFDOVWRFDXVHDGYHUVHKHDOWKHIIHFWV HGDUHRIWHQSUHFHGHGE\DQGUHVXOWIURPDOWHUDWLRQVLQJHQH RQ7R[LFDQW LQGXFHGFKDQJHV LQJHQHH[SUHVVLRQDUHSRWHQ G WKDW WRROVDUH UHTXLUHG WRDOORZPXOWLSOHYDULDEOHV VXFKDV
H[SUHVVLRQ WR EH FRQVLGHUHG VLPXOWDQHRXVO\8QWLO UHFHQWO\ KZDVWRH[DPLQHWKHHIIHFWVRIFKHPLFDOVRQRQHRUDQRWKHU D WLPH E\ ZHOOHVWDEOLVKHG WHFKQRORJLHV VXFK DV HQ]\PDWLF U1RUWKHUQRU:HVWHUQEORWWLQJ7KHUHKDYHEHHQYHU\ ODERU HIIRUWVWRGHWHUPLQHWKHYDULRXVVWHSVLQELRFKHPLFDOSDWKZD\V
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
R[LFDQWV:HDUHQRZHQWHULQJDQHZSKDVHLQWKHELRVFLHQFHV H LQIRUPDWLRQ LV QR ORQJHU OLPLWLQJ :DWHUVWRQ DQG6XOVWRQ QRORJLHVDUHDYDLODEOHWRWDFNOHWKHPDMRUFKDOOHQJHVLQWR[L HGHYHORSPHQWRIQHZ LQ YLWUR DVVD\V ,Q WKHSDVWÀYH\HDUV LÀFDQWSURJUHVV LQ ODUJHVFDOHJHQRPHVHTXHQFLQJDQG LQ WKH QLFDOSODWIRUPVWRVXSSRUWWKLV6HYHUDOJHQRPHVVXFKDVWKH WLF \HDVW6DFFKDURP\FHV FHUHYLVLDH 'H5LVL HW DO DQG PDWRGH&DHQRUKDEGLWLV HOHJDQV 7KH& HOHJDQV VHTXHQFLQJ KDYHQRZEHHQFRPSOHWHO\VHTXHQFHGDQGVHTXHQFLQJRIWKH HLVDQWLFLSDWHGWREHFRPSOHWHVRRQDVWKHUHVXOWRIVLJQLÀFDQW HQW E\ERWK WKH DFDGHPLF DQG LQGXVWULDO VHFWRUV :DWHUVWRQ
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À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
'1$PLFURDUUD\ SRWHQWLDOO\ WKRXVDQG 7KLVIDFLOLWDWHVIRU FRQWUROZLWK FKHPLF LQYROYHVWKHLPPRE FOHRWLGHVZKLFK FR
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ÀHGIROORZLQJH[SUHVVLRQE\ WKHHQWLUHJHQRPH WLPH 6LQFH JHQRPH VHTXHQFHV FDQ EH XVHG WR SUHGLFW WKH SURGXFWV WKH ZHDOWK RI LQIRUPDWLRQ LQ WKLV DUHD SURYLGHV DQ IRUXQGHUVWDQGLQJFHOOXODU IXQFWLRQ LQPDPPDOVDW WKHSURWHLQ H EHWZHHQPROHFXODU ELRORJ\ DQG SURWHLQ ELRFKHPLVWU\ SUR FDOHVFUHHQLQJRISURWHLQVH[SUHVVHGE\DJHQRPHLQDQRUJDQ OO:LONLQVHWDO&HOLVDQG*URPRY3URWHRPLFV RQVEHWZHHQGLIIHUHQWSURWHRPHVLQRUGHUWRGHWHUPLQHSDWWHUQV WKDWFKDUDFWHUL]HDVSHFLÀFELRORJLFDOSURFHVV&HOLVDQG*UR PRUH WKLV FRPSOHPHQWV JHQRPLFVEDVHG DSSURDFKHV VLQFH LW DOLQIRUPDWLRQRQSURWHLQH[SUHVVLRQSURWHLQWXUQRYHUUDWHDQG GLÀFDWLRQV VXFK DV SKRVSKRU\ODWLRQ RU DFHW\ODWLRQ WKDW DOWHU \RISURWHLQV$QH[DPSOHLVWKHYDVWQXPEHURIFRPELQDWLRQV PRGLÀFDWLRQV REVHUYHG RQ KLVWRQH SURWHLQV DQG WKHLU FRQVH DWLRQRIJHQHH[SUHVVLRQ6WUDKODQG$OOLVZKLFKHPSKD RI WDNLQJLQWRDFFRXQW WKHQDWXUHRIPDWXUHJHQHSURGXFWVDV $,QDGGLWLRQLWLVSUREDEOHWKDWSURWHLQSKRVSKRU\ODWLRQZLOO QVHTXHQWLDOFKDQJHVLQJHQHH[SUHVVLRQZKLFKZLOOEHGHWHFW \VLV$OWKRXJKSURWHRPLFVLVQRW\HWDKLJKO\DXWRPDWHGSURFHVV WKHDGYDQWDJHVDQGLPSRUWDQFHRIGLUHFWO\DQDO\]LQJSURWHLQV HQW IRU FRPELQLQJ WKHVH WZR DSSURDFKHV ,Q WKLV UHYLHZZH VWDWXV LQ WKH WR[LFRORJLFDO VFLHQFHVRI WKHVH WZRKLJKO\FRP JLHV
MICROARRAY TECHNOLOGIES
VDOORZTXDQWLWDWLYHFRPSDULVRQVRIWKHH[SUHVVLRQOHYHOVRI
VRI LQGLYLGXDOJHQHVEHWZHHQGLIIHUHQWELRORJLFDO VDPSOHV LQVWDQFHFRPSDULVRQVRIQRUPDOWLVVXHZLWKGLVHDVHGDQGRI DO WUHDWHG FHOO OLQHV RU WLVVXHV&RQVWUXFWLRQRIPLFURDUUD\V LOL]DWLRQRINQRZQ'1$VHTXHQFHVHLWKHUF'1$RUROLJRQX UUHVSRQG WR WKH FRGLQJ VHTXHQFH RI JHQHV RI LQWHUHVW RQ D
VROLG VXSSRUW VXFK P51$SUHSDUHGIUR WKH IRUP RI D UHYH XVLQJ SKRVSKRULPD VRXUFHV FDQ EH ODEH FXUUHQWO\ZLWKFRP FHQFH VFDQQLQJ LV &KDQJHVLQP51$O VLRQ RIZKLFK LV DV SRVVLEOHGLIIHUHQW OH 6XEVHTXHQWELRLQIR WLRQ RI WKH H[WHQW R DUUD\HG F'1$ VSR TXDQWLWDWLYHDVVHVVP %URZQDQG%RWVWHL \VLVSURJUDPVGDWD IRUWUDQVFULSWSURÀOL ([SUHVVLRQSURÀOLQJ LFLW\SHUPLWWLQJDQD UHYHDOLQJVSHFLHVVS QRORJ\SURYLGHVDS H[SUHVVLRQDVVRFLDWH \VHVPD\UHYHDOSD XQGHUVWDQGLQJRIWK RIVHQVLWLYHDQGVSH
0DQ\ FRPPHUFL VHYHUDO KXQGUHG JHQ ZLWK UDGLRODEHOHGF RWLGHVHTXHQFHVLP SUREH WHFKQRORJ\ PLFURDUUD\VZLOOGHS WLYH 7KH LQGXFWLYH DQG LPSOLFDWH WKHP H[SUHVVLRQ RI ODUJH DQGH[SUHVVHGVHTX WXUHV IRU WR[LFDQWV SDUWLFXODUELRORJLFD WLRQ DUH LQFRUSRUDWH ZKHQ VRPH LQIRUPD FRXUVH DQ DOWHUQDWL NQRZQIXQFWLRQVDQG PLFURDUUD\VFDQHLWK WLVVXHV ELRORJLFDO S GHVLJQHGWRSURÀOHJ E\ FRPPHUFLDO YHQ GHPLFLQVWLWXWLRQV
DV D JODVV VOLGH RU Q\ORQ PHPEUDQH %RZWHOO 7KH PFHOOVRU WLVVXHVFDQEH ODEHOHGDQGK\EULGL]HGXVXDOO\ LQ UVH WUDQVFULEHG F'1$ FRS\ WR D PLFURDUUD\ DQG YLVXDOL]HG JHU VFDQQLQJ $OWHUQDWLYHO\ F'1$V IURP WHVW DQG FRQWURO OHGZLWK WZR GLIIHUHQW ÁXRUHVFHQW WDJV DQG K\EULGL]HG FRQ SOHPHQWDU\VHTXHQFHVRQ WKHVDPHPLFURDUUD\+HUHÁXRUHV XVHG WR LGHQWLI\ GLIIHUHQWLDO FKDQJHV LQ P51$ H[SUHVVLRQ HYHOVDUHQRUPDOL]HGDJDLQVWKRXVHNHHSLQJJHQHVWKHH[SUHV VXPHG WR EH VWDEOH DQG LQGHSHQGHQW RI WUHDWPHQW WR UHÁHFW YHOVRI ODEHOLQJRI WKH WHVW DQGFRQWUROP51$SRSXODWLRQV UPDWLFDQDO\VHVXVLQJDSSURSULDWHVRIWZDUHDOORZVGHWHUPLQD I K\EULGL]DWLRQ RI WKH ODEHOHG SUREHV WR WKH FRUUHVSRQGLQJ WV DQG D FRPSDULVRQ RI FRQWURO ZLWK WHVW VDPSOHV SHUPLWV HQWRIFKDQJHVLQJHQHH[SUHVVLRQDVVRFLDWHGZLWKWUHDWPHQW Q7KHGHYHORSPHQWRIVSHFLÀF'1$PLFURDUUD\DQDO PLQLQJ WHFKQRORJLHV DQG UHIHUHQFHGDWDEDVHV LV LPSHUDWLYH QJH[SHULPHQWVWREHSUDFWLFDODQGVFLHQWLÀFDOO\PHDQLQJIXO FRXOGSRWHQWLDOO\IRFXVRQLPSRUWDQWPDUNHUJHQHVIRUWR[ O\VLVRIVDPSOHVIURPERWKKXPDQDQGURGHQWFHOOVWKHUHE\ HFLÀFHIIHFWV7KXVWKHDSSOLFDWLRQRI'1$PLFURDUUD\WHFK RZHUIXOWRROLQLGHQWLI\LQJDQGFKDUDFWHUL]LQJFKDQJHVLQJHQH GZLWKVSHFLÀFWR[LFDQWVRUIDPLOLHVRIWR[LFDQWV6XFKDQDO WWHUQVRIJHQHH[SUHVVLRQFKDQJHV WKDWZRXOGERWKDVVLVWRXU HSRVVLEOHPHFKDQLVPVRIWR[LFLW\DQGDOORZWKHLGHQWLÀFDWLRQ FLÀFHDUO\PDUNHUV DOPLFURDUUD\V DUH DYDLODEOH YDU\LQJ IURP WKRVH FRPSULVLQJ HV XVXDOO\ LPPRELOL]HG RQ D Q\ORQPHPEUDQH DQG SUREHG '1$ WR WKRVH UHSUHVHQWLQJ WHQVRI WKRXVDQGVRIROLJRQXFOH PRELOL]HGRQJODVVVOLGHVDQGDQDO\]HGXVLQJGXDOÁ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
HUEHEURDGVSHFWUXPRUFXVWRPGHVLJQHGWRSURÀOHSDUWLFXODU DWKZD\V RU HYHQ GLVHDVH VWDWHV ,Q WKLV UHJDUGPLFURDUUD\V HQHVLQYROYHGLQUHVSRQVHVWRWR[LFLQVXOWKDYHEHHQGHYHORSHG GRUV SKDUPDFHXWLFDO DQG DJURFKHPLFDO FRPSDQLHV DQG DFD )LJXUH1XZD\VLUHWDO3HQQLH
3URWHRPLFVFDQE WRXQGHUVWDQG WKHVWD SURWHLQVUHJXODWHGE\ WZRSULQFLSDOVWHSV GLPHQVLRQDOSRO\DFU\ SOHPHQWRIFHOOH[WUD DQG PROHFXODU ZHLJ SURWHLQVRQDVLQJOH WKH VHSDUDWHG SURWHL ELRLQIRUPDWLFVDQG WUHDWPHQWRIDFHOORU KLJKWKURXJKSXWVWXG GHYHORSHG\HDUVD QRZEHDFKLHYHGIRU ELOL]HG S+ JUDGLHQWV FKHPLFDOO\ LPPREL LPSURYHPHQWV LQ WKH DEXQGDQWSURWHLQV7 SXWHU DQDO\VLV SURJU DOORZV WKH ELRLQIRUP :LONLQVHWDO
6LOYHUVWDLQLQJD RGVRIGHWHFWLRQDQ UHOLDEOHTXDQWLWDWLYH LGHQWLI\LQJ SURWHLQV SURWHRPLFVLVDQHZ LPSRUWDQFHLQWKHOL WKH FRQWLQXHG UDSLG EHFRPH D ODUJHVFDO ZLWK JHQRPLFV WKH EHHQFULWLFDOWRWKHG WR DOORZ WKH FRPSDU GHJUDGDWLRQ EHWZHHQ SURWHRPHFKDQJHVLQ LGHQWLI\H[SUHVVLRQ 7KHDSSOLFDWL VLJQDOLQJSDWKZD\V VRSKLVWLFDWHG LQYLWU GLUHFWO\DQDO\]LQJS 7KHVKRUWFRPLQJVR RIDSURWHLQHTXLYDO LPSURYHGDXWRPDWLR OHQJHVZLOO XQGRXEW RIWKHLPSRUWDQFHR
PROTEOMIC TECHNOLOGIES
HGHÀQHGDVWKHVLPXOWDQHRXVDQDO\VLVRIPDQ\SURWHLQVLQRUGHU WHRIDFHOORUD WLVVXH ,WRIIHUV WKHSRVVLELOLW\RI LGHQWLI\LQJ [HQRELRWLFVZLWKRXWSULRUELDVWRFODVVRUIXQFWLRQ7KHUHDUH WKHÀUVWLVWRVHSDUDWHSURWHLQVLQDVDPSOHXVXDOO\XVLQJWZR ODPLGHJHOHOHFWURSKRUHVLV'3$*(7KHWRWDOSURWHLQFRP FWVLVDQDO\]HGDFFRUGLQJWRLVRHOHFWULFSRLQWÀ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ÁXRUHVFHQWG\HVZKLFKZLOOSURYLGH DQDO\VLVKDYHEHHQGHYHORSHGUHFHQWO\(DFKVWHSLQYROYHGLQ KDV OLPLWDWLRQV WKDW PDNH DXWRPDWLRQ GLIÀFXOW 7KHUHIRUH HQDEOLQJWHFKQRORJ\EXWWKHUHLVDJURZLQJUHDOL]DWLRQRILWV IHVFLHQFHV7KLVLQFUHDVHGDWWHQWLRQDQGLQYHVWPHQWZLOOIXHO DGYDQFH RI WKLV WHFKQRORJ\ DQG VKRXOG DOORZSURWHRPLFV WR H KLJKO\ DXWRPDWHG SURFHVV LQ WKH QHDU IXWXUH ,Q FRPPRQ DYDLODELOLW\ RI DQ LQFUHDVLQJO\ FRPSUHKHQVLYH GDWDEDVH KDV HYHORSPHQWRISURWHRPLFV7KLVWHFKQRORJ\KDVWKHSRWHQWLDO LVRQRI DOO FKDQJHV LQ SURWHLQ H[SUHVVLRQPRGLÀFDWLRQ DQG WUHDWHG DQG XQWUHDWHG VDPSOHV DQG WR FRPSDUH SDWWHUQV RI GXFHGE\FRPSRXQGVZLWKVLPLODUWR[LFRORJLFDOHQGSRLQWVWR SURÀOHVVSHFLÀFIRUIDPLOLHVRIWR[LFDQWV:DQJDQG+HZLFN RQRISURWHRPLFVWRWKHELRORJ\RIURGHQWVPD\KHOSWRLGHQWLI\ LQYROYHG LQ WKHPRGHRI DFWLRQRI WR[LFDQWV OHDGLQJ WRPRUH RDVVD\VIRUWKHLUDFWLYLW\7KHDGYDQWDJHVDQGLPSRUWDQFHRI URWHLQVPDNHDVWURQJDUJXPHQW IRU WKHYDOXHRISURWHRPLFV
IWKURXJKSXWDQGVHQVLWLYLW\LQFOXGLQJIRU LQVWDQFHWKHODFN HQWIRU WKHSRO\PHUDVHFKDLQUHDFWLRQKLJKOLJKW WKHQHHGIRU QHQULFKPHQW DQGGHWHFWLRQPHWKRGV7KHVH WHFKQLFDOFKDO HGO\ EH WDFNOHG DQGRYHUFRPHZLWK WKH LQFUHDVHG DZDUHQHVV ISURWHRPLFV)LJXUH
$V WKH IXOOOHQJW DUH LQFUHDVLQJ RSSR UHVSRQG WR WR[LFDQWV SRZHUIXOWRROLQLGHQ ZLWKWR[LFLW\,QRUGH VFLHQFHV WKH IROORZ QHFHVVDULO\UHÁHFWHG WKH GHWHFWDEOH SDWWHU FRPSUHKHQVLYHWRSH QRWVRFRPSOH[WKDW WKDW LQ SUDFWLFH UHODW UHVSRQVHV )DUUDQG NLQHWLFVRILQGXFWLRQ WKHJHQRPLFVDSSURD FDQGLGDWHV$OWKRXJK DOUHDG\EHHQXVHGVX UDQJLQJIURPLQÁDPP VXSSUHVVLRQ'H5LVL 6FKHUIHWDO
7KHELRORJLFDO UH FOHDUO\RIPDMRULPS RUDPRGHRIDFWLRQ DSK\VLRORJLFDOKLVW YLWURRU LQYLYRFDQ DQH[DPSOHQRQJHQR WHUPFDQFHUELRDVVD\ DVSURWHRPLFDSSOLF PHQW RI WKLV SKHQR QRQJHQRWR[LFFDUFLQR JHOEDVHGH[SUHVVLRQ H[SUHVVLRQLVPRGXOD
,QDQRWKHUVWXG\ UD\RIXQNQRZQKXP FDUFLQRJHQ SKRUERO H[SUHVVLRQOHYHOVLQ LQGXFHGJHQHVE\SKR N%DQG3$&W\U F\FOHUHJXODWLRQ6FK UHVSRQVHRIDKXPDQ &&OXVLQJDFXVWRP IRXQGWKDW&&OFDXV ZDV DVVRFLDWHG VRP SURWHLQ+ROGHQHWD DSSOLHGLQRXUODERUD
TOXICOGENOMICS APPLICATIONS
K VHTXHQFHRI VHYHUDOPDPPDOLDQJHQRPHV LV UHYHDOHG WKHUH UWXQLWLHV WR GHWHUPLQH KRZ GLIIHUHQW PDPPDOLDQ JHQRPHV 7KH DSSOLFDWLRQ RI '1$PLFURDUUD\ WHFKQRORJ\ SURYLGHV D WLI\LQJDQGFKDUDFWHUL]LQJFKDQJHVLQJHQHH[SUHVVLRQDVVRFLDWHG UIRU'1$PLFURDUUD\WHFKQRORJ\WREHXVHIXOLQWR[LFRORJLFDO LQJ WZR DVVXPSWLRQV PXVW EH PDGH )LUVW WR[LF LQVXOWV DUH GLUHFWO\RULQGLUHFWO\E\FKDQJHVLQJHQHWUDQVFULSWLRQ6HFRQG Q RI LQGXFHG FKDQJHV LQ JHQH H[SUHVVLRQZLOO EH VXIÀFLHQWO\ UPLWWKHLGHQWLÀFDWLRQRILPSRUWDQWSDWKZD\VDQGPDUNHUVEXW PHDQLQJIXODQDO\VLVLVSURKLELWHG,QGHHGLWKDVEHHQSURSRVHG LYHO\ IHZ SDWWHUQV RI JHQH H[SUHVVLRQ GHÀQH HOHPHQWDO WR[LF 'XQQ6LQFHP51$VYDU\ LQ WKHLUG\QDPLF UDQJHDQG FRPSUHKHQVLYHDQGFDUHIXOO\GHVLJQHGVWXGLHVVKRXOGLQWHJUDWH FKZLWK1RUWKHUQEORWWLQJRU573&5RIDVKRUWOLVWRILQWHUHVWLQJ '1$PLFURDUUD\ LV VWLOO D UHODWLYHO\ QHZ WHFKQRORJ\ LW KDV FFHVVIXOO\ WR LQYHVWLJDWHDOWHUHGJHQHH[SUHVVLRQ LQSURFHVVHV DWRU\GLVHDVHWRLQGXFWLRQRIVHQHVFHQFHWRFDQFHUDQGWXPRU HWDO+HOOHUHWDO6KHOWRQHWDO5RVVHWDO OHYDQFHRI WKH H[SHULPHQWDO V\VWHP IRU WUDQVFULSWSURÀOLQJ LV RUWDQFHZKHUHDPHFKDQLVWLFXQGHUVWDQGLQJRIDWR[LFSURFHVV LVUHTXLUHG:KHUHWKHWR[LFHQGSRLQWLVNQRZQLQDGYDQFHDW RORJLFDORUELRFKHPLFDO OHYHO DQDSSURSULDWH WHVW V\VWHP LQ EHGHVLJQHGWRPRGHO WKHHQGSRLQWDVFORVHO\DVSRVVLEOH$V WR[LFFDUFLQRJHQHVLVLVXVXDOO\HYDOXDWHGLQWKHFRQWH[WRIORQJ VLQURGHQWV&KDEUDHWDO7UDQVFULSWSURÀOLQJDVZHOO DWLRQVPD\KHOSWRLGHQWLI\VXUURJDWHPDUNHUVIRUWKHGHYHORS W\SH DQG LQGHHG WKH H[SRVXUH RI URGHQW KHSDWRF\WHV WR WKH JHQSKHQREDUELWDOKDVEHHQVWXGLHGXVLQJERWKPLFURDUUD\DQG WHFKQRORJLHV,QH[FHVVRIJHQHVKDYHEHHQLGHQWLÀHGZKHUH WHGE\WKLVFRPSRXQG5RGLHWDO DQRYHOJHQHZDVGLVFRYHUHGE\XVLQJDHOHPHQWPLFURDU DQF'1$V WR H[DPLQHKRZ WUHDWPHQWZLWK WKHQRQJHQRWR[LF P\ULVWDWH DFHWDWH SKRUERO HVWHU 30$ DIIHFWV P51$ KXPDQ7-XUNDWFHOOV6FKHQDHWDO7KHPRVWKLJKO\ UEROHVWHUVZHUHWKHQXFOHDUWUDQVFULSWLRQIDFWRUNDSSD%1) RVLQHNLQDVHDOVRLQYROYHGLQUHJXODWLQJWUDQVFULSWLRQDQGFHOO HQDHWDO,QRXUODERUDWRU\+ROGHQHWDOH[DPLQHGWKH KHSDWRPDFHOOOLQHWRWKHKHSDWRWR[LFDQWFDUERQWHWUDFKORULGH
JHQHV'1$PLFURDUUD\+ROGHQHWDO7KH\KDYH HVDUDSLGLQFUHDVHLQLQWHUOHXNLQP51$H[SUHVVLRQDQGWKLV HZKDW ODWHU E\ DQ LQFUHDVH LQ WKH OHYHO RI WKH FRUUHVSRQGLQJ O$PRQJ WKHDUHDVZKHUH WUDQVFULSWSURÀOLQJ LVEHLQJ WRU\DUHWKHIROORZLQJ
7KHVH VWXGLHV LO LGHQWLÀFDWLRQRIQRY 0DQ\ RWKHU WR[LF HQ FRPELQDWRULDO DSSUR SRWHQWLDOO\SURYLGLQJ
'HVSLWHWKHIDFWW JHQHSURGXFWVLWLVD LVQRORQJHUWHQDEOH HGLWLQJDQGSRVWWUD HQYLURQPHQWZKHUH DQGHYHQWXDOO\GHJU DQGÀ[HGEXWLWLVH XSWRVL[IRUDSUHGL LWKDVEHHQHVWLPDWH IROGPRUHSURWHLQVJ KDVDOUHDG\EHHQXVH GLVHDVHDQGFDQFHU H[DPSOHVRIVWXGLHV H[SUHVVLRQRFFXUXS HQYLURQPHQWZKLFK XQFRYHUHGE\WKLVWH HIIHFWVKDYHVKRZQW E\DFRPSRXQGSURY )RUH[DPSOHWKHWR[ WKHWUHDWPHQWRIVRP WUDQVSODQWDWLRQLQUD 7ZRGLPHQVLRQDOJH KDYHVKRZQWKDWRQH LQ FDOFLXP ELQGLQJ IDLOXUHWRH[FUHWHFDO RI&V$LQURGHQWV$ SDOPLWR\OWUDQVIHUDVH UHODWHGSURWHLQ$'5
OXVWUDWH WKH SRWHQWLDO RI '1$ PLFURDUUD\ WHFKQRORJ\ LQ WKH HOJHQHFKDQJHVDVVRFLDWHGZLWKWR[LFSURFHVVHV3HQQLH GSRLQWV FRXOG EH SURÀOHG XVLQJ WKLVPHWKRG DVVRFLDWHGZLWK DFKHV VXFK DV WUDQVJHQLF RU NQRFNRXWPRGHOV 5\IIHO LQVLJKWVLQWRWKHUROHRIVSHFLÀFJHQHV
PROTEOMICS APPLICATIONS
KDWJHQRPHVHTXHQFHVFDQEHXVHGWRSUHGLFWWKHFRUUHVSRQGLQJ SSDUHQWWKDWWKHSDUDGLJPRIRQHJHQHHQFRGLQJDVLQJOHSURWHLQ EHFDXVHRISURFHVVHVVXFKDVDOWHUQDWLYHP51$VSOLFLQJ51$ QVODWLRQDOSURWHLQPRGLÀFDWLRQ7KHFHOO LQWHULRU LVDG\QDPLF P51$DQGSURWHLQVDUHSHUSHWXDOO\EHLQJV\QWKHVL]HGPRGLÀHG DGHG7KHQXPEHURIJHQHV LQ DQ LQGLYLGXDOPDPPDO LV VWDWLF VWLPDWHGWKDWWKHDYHUDJHQXPEHURISURWHLQVSHUJHQHFRXOGEH FWHGWRWDORIJHQHVLQKXPDQV:LONLQV,QIDFW GWKDWDVLQJOHFHOOH[SUHVVHV²JHQHVZLWKVHYHUDO LYHQWKHHIIHFWVRISRVWWUDQVODWLRQDOPRGLÀ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ÀOHVRISURWHLQV LVRODWHG IURPDNLGQH\ WUHDWHGZLWK&V$ RIWKHSURWHLQVGRZQUHJXODWHGLVFDOELQGLQDPROHFXOHLQYROYHG
DQG WUDQVSRUW 7KH ORVV RI FDOELQGLQ DSSDUHQWO\ DFFRXQWV IRU FLXPGHSRVLWVLQWKHNLGQH\DQGFRXOGH[SODLQWKHQHSKURWR[LFLW\ LFKHUHWDO(WRPR[LUDUHYHUVLEOHLQKLELWRURIFDUQLWLQH FDXVHVDFFXPXODWLRQLQOLYHURIWKHDGLSRF\WHGLIIHUHQWLDWLRQ 3DSURWHLQWKRXJKWWRFORWKHWKHOLSLGGURSOHWVWKDWDFFXPXODWH
DVDUHVXOWRIWKHEOR $LFKHUHWDO
7KHURGHQWOLYHU 33VLQYROYHVFKDQJ EHHQVWXGLHGE\WZR PDQQHWDO$ DE&KHYDOLHUH EHHQVKRZQWREHDO WKH HQR\O&R$K\GU 3%( WKHF\WRVROLF WKHK\GUR[\PHWK\OJ WHLQ DQG WKH F\WRFK SURWHLQV FRQWDLQSHU PRWHU UHJLRQV RI WK SHUR[LVRPH SUROLIHUD PHWDEROLFUHVSRQVHW DQGWXPRULJHQHVLV& WHRPLFVSURWHLQV WKHK\SROLSLGDHPLF3 FKROLQHUHFHSWRULQ &KHYDOLHU HW DO SURWHLQVLVUHJXODWHG UHVSRQVHVWKDWUHJXOD LQLWLDO 33$5EPHGLD SURWHLQWDUJHWVPD\R E\ 33V DQG RSSRUWX SRWHQWLDO FDUFLQRJHQ DQWDJRQLVW PHWKDS\U GLVFRYHU\RILWVSRWHQ FRYDOHQWPRGLÀFDWLR RIDUHDFWLYHGUXJP KDPHWDO7K XQGHUVWDQGLQJRI WKH WR[LFFDUFLQRJHQV7K EHWZHHQGUXJWUHDWP UHVXOWLQJSDWKRSK\VL WKH\FRXOGEHDSSOLH WKHGLVFRYHU\RIQRY
THE C
7KHSRVVLELOLW\WK HQGSRLQWPHFKDQLVP FKDQJHV LQ JHQH H[S SUHGLFWLYHWR[LFRORJ\
FNLQJHIIHFWRI&V$RQOLSLGPHWDEROLVP6WHLQHUHWDO
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ÀHGLQFOXGLQJWKHPXVFDULQLFDFHW\O WHUPHGLDWHÀODPHQWYLPHQWLQDQGWKHFVXEXQLWRI$73V\QWKDVH ,W LV QRW NQRZQ\HWZKHWKHU WKH H[SUHVVLRQ RI WKH DERYH GLUHFWO\E\33$5ERUZKHWKHUWKHUHH[LVWVDFDVFDGHRIOLQNHG WHH[SUHVVLRQRIWKHVHSURWHLQVDVVHFRQGDU\HYHQWVIROORZLQJ WHG DOWHUDWLRQV LQ SURWHLQ H[SUHVVLRQ7KHVH QRQSHUR[LVRPDO IIHULQVLJKWVLQWRWKHPHFKDQLVPVRIFDUFLQRJHQHVLVLQURGHQWV QLWLHV WR LGHQWLI\ PDUNHUV WR IDFLOLWDWH HDUO\ LGHQWLÀFDWLRQ RI V$QRWKHU H[DPSOH LVSURYLGHGE\ WKHKLVWDPLQH+ UHFHSWRU LOHQH ZKLFK ZDV ZLWKGUDZQ IURP WKHUDSHXWLF XVH IROORZLQJ WQRQJHQRWR[LFKHSDWRFDUFLQRJHQLFLW\LQUDWV7KLVGUXJFDXVHV QRID VHULHVRIPLWRFKRQGULDOSURWHLQVSRLQWLQJ WR WKHDFWLRQ HWDEROLWHLQWKHPLWRFKRQGULD$QGHUVRQHWDO&XQQLQJ HVHSURWHRPHSURÀOLQJH[SHULPHQWVFRQWULEXWHWRDQHQKDQFHG PROHFXODUPHFKDQLVPVLQYROYHG LQ WKHUHVSRQVH WRQRQJHQR HVHDQGRWKHUH[DPSOHVVWURQJO\LPSO\IXQFWLRQDOUHODWLRQVKLSV HQWSURWHLQH[SUHVVLRQGHWHFWHGE\WZRGLPHQVLRQDOJHOVDQG RORJLFDO HIIHFWV:KLOH SURWHRPLF VWXGLHV DUH LQ WKHLU LQIDQF\ GWRPDQ\WR[LFRORJLFDO LVVXHVDQGWKH\DUH OLNHO\WRUHVXOW LQ HOWR[LFRORJLFDOUHVHDUFKOHDGVDQGGLDJQRVWLFPDUNHUV
HALLENGE OF PATTERN RECOGNITION
DWDVSHFLÀFJURXSRUFODVVRIFRPSRXQGVDVGHÀQHGE\WR[LF VWUXFWXUHRU WDUJHWRUJDQPD\ LQGXFHVLJQDWXUHSDWWHUQVRI UHVVLRQ LV RQH EDVLV IRU WKH DSSOLFDWLRQ RI WR[LFRJHQRPLFV WR ([SRVXUHWRGLIIHUHQWFODVVHVRIWR[LFDQWVLVOLNHO\WRUHVXOWLQ
GLVWLQFWSDWWHUQVRID WXQLW\IRUÀQJHUSULQW 7UDQVFULSW DQG SURWH WKHVHHIIHFWVWKURXJK WXUHV LQ H[SRVHG DQ SDWWHUQVFRXOGEHGH FDQGLGDWH FRPSRXQG VXFKSURÀOLQJH[SHUL LQUHVSRQVHWRDFXWH PLQLQJNH\SDUDPHWH DQGWLPHSRLQWWREH FKDUDFWHUL]HGIRUNQ V\VWHPZLWKDQXQN HVWDEOLVKHGDQGWKHUH WR[LFJURXS
0RUHRYHU LW LVS RU'1$PXWDWLRQZ PD\H[KLELWGLIIHUHQ FRPSLOLQJGDWDVHWV LQJHQHRUSURWHLQH UHFRJQLWLRQPD\LQW WRGHWHFWVSHFLÀFWR[ SRWHQWLDODGYHUVHKH LQSUHGHYHORSPHQWWR DQHDUO\YLHZRIFR RIUHIHUHQFHGDWDVHW WRUHTXLUHWKHDSSOLFD )RUH[DPSOHVWDWLVWL WRDQDO\]HWKHWHPSR VLYHQHVV DQGZRXQG IURPQRUPDOWLVVXHV VHWVSRVVLEO\E\FRP GHPDQG FRQVLVWHQF\ ERWKWKHDFDGHPLFDQ %DVVHWWHWDO
OPPORT
7KHUHLVDQLQFUH PHWKRGV IRU WKH LG DELOLW\ QRZ WR GHÀQ LQGXFHGLQFHOOVE\W SURYLGHV H[FLWLQJ DSSURDFKHVWRVDIHW\ IRUPVDQGELRORJLFD
OWHUHGP51$DQGSURWHLQH[SUHVVLRQDQGWKLVRIIHUVWKHRSSRU LQJWR[LFDQWVRIDSDUWLFXODUW\SH6WHLQHUDQG$QGHUVRQ RPH SURÀOLQJ VWXGLHV FDQ EH XVHG WR FDWHJRUL]H DQG FODVVLI\ WKHGLUHFWFRPSDULVRQRIP51$RUSURWHLQH[SUHVVLRQVLJQD G FRQWURO VDPSOHV 3RWHQWLDOO\ P51$ RU SURWHLQ H[SUHVVLRQ WHUPLQHGIRUYDULRXVW\SHVRIWLVVXHVSHFLÀFWR[LFDQWVDOORZLQJ V WR EH VFUHHQHG IRU WKHVH FKDUDFWHULVWLF SDWWHUQV 0RUHRYHU PHQWVPLJKWEHSDUWLFXODUO\XVHIXOWRLQYHVWLJDWHWKHGLIIHUHQFHV DQGFKURQLFWR[LFLW\6XFKLQYHVWLJDWLRQVFRXOGDVVLVWLQGHWHU UVVXFKDVDSSURSULDWHH[SHULPHQWDOPRGHOVDQGFKRLFHRIGRVH VWHOXFLGDWHPHFKDQLVPV2QFHDQH[SUHVVLRQVLJQDWXUHKDVEHHQ RZQWR[LFDQWV LQDGHÀQHGELRORJLFDOPRGHO WUHDWPHQWRI WKDW QRZQDJHQWPD\DFWLYDWHDSDWWHUQRIJHQHH[SUHVVLRQDOUHDG\ IRUHLGHQWLI\WKLVDJHQWDVDFKHPLFDOEHORQJLQJWRDSDUWLFXODU
RVVLEOH WRDQDO\]HVHTXHQFHYDULDWLRQVVXFKDVSRO\PRUSKLVP LWKROLJRQXFOHRWLGHEDVHGPLFURDUUD\VWRVFUHHQLQGLYLGXDOVWKDW WLDOELRORJLFDOUHVSRQVHV+DFLDDQG&ROOLQV7KHUHIRUH RIWR[LFDQWH[SRVXUHVFRXOGDOORZHVWLPDWLRQRIWKHYDULDELOLW\ [SUHVVLRQEHWZHHQLQGLYLGXDOVLQUHVSRQVHWRWR[LFDQWV3DWWHUQ XUQDOORZWKHGHVLJQDQGFRQVWUXFWLRQRIFXVWRPL]HGPLQLDUUD\V LFLW\HQGSRLQWVRUSDWKZD\V,IWKHVHV\VWHPVZHUHDEOHWRGHWHFW DOWKHIIHFWVRIVRPHGHYHORSPHQWFRPSRXQGVWKHLUDSSOLFDWLRQ [LFRORJ\VFUHHQLQJZRXOGEHRIVXEVWDQWLDOEHQHÀ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
UNITIES IN COMBINATION: A PERSPECTIVE
DVLQJGHVLUHDQGQHHGWRGHYHORSDFFXUDWHDQGUREXVWLQYLWUR HQWLÀFDWLRQ DQG FKDUDFWHUL]DWLRQ RI SRWHQWLDO WR[LFDQWV 2XU
H LQ DPRUH KROLVWLF IDVKLRQ WKHPROHFXODU FKDQJHV WKDW DUH UDXPDGDPDJHRURWKHUSHUWXUEDWLRQVRISK\VLRORJLFDOEDODQFH RSSRUWXQLWLHV WR H[SORUH QHZ IUDPHZRUNV IRU DOWHUQDWLYH DVVHVVPHQW,QGHHGWKHGHYHORSPHQWRIELRWHFKQRORJ\SODW OVFLHQFHVLVDPDMRUIDFWRULQWKHDGYDQFHPHQWRIDOWHUQDWLYH
WHVWLQJPHWKRGRORJL DQRUJDQLVPWRDFK PDWLRQEXW LW LVEHF LV GLIÀFXOW WR SUHGLF DQG SURWHRPLFV RII JHQRPH H[SUHVVHG $QGHUVRQ&O DQHDUO\DOHUWWRSRWH UDLVHVPDQ\ LVVXHV UHVSHFW WRKD]DUGDQ LQ UHVSRQVH WR WR[LF KHDOWKHIIHFWVWKDWDU WRDQWLFLSDWHWKDWLQW ZLOORQO\EHSRVVLEOH DQG FRQGXFWHG DV S WR[LFLW\DW WKHSK\VL ZLWKWKHYDVWDPRXQ WRFRPSRXQGVLQURG
3URWHRPLFV DQG UHTXLUHWR[LFRORJLVWV LV LQHYLWDEOH WKDWZK YHU\IHZJHQHVH[LVWV H[SHFWDWLRQVRUSUHM RIXVLVWKDWFRQVLGH ZHUHEHOLHYHG WREH DQGFRQVLGHUDWLRQRI 2QHFRXOGSUHGLFWWKD ZLOOGHULYHIURPWKH DQGSURWHRPLFVZLOO FDUHIXODQGLQWHJUDWHG SRZHUIXOWHFKQRORJLH DQGWKHUHIRUHQHZRS
HV3XUFKDVHHWDO5HVSRQVHVRIDFHOOXODUV\VWHPRU HPLFDORUD WR[LFDQW LQYROYH WKHH[SUHVVLRQ RIJHQHWLF LQIRU RPLQJ LQFUHDVLQJO\FOHDU WKDW WKHEHKDYLRURIJHQHSURGXFWV W IURP JHQH VHTXHQFH 7KH FRPELQDWLRQ RI WR[LFRJHQRPLFV HUV VFLHQWLVWV WKH DELOLW\ WR LQWHJUDWH LQIRUPDWLRQ IURP WKH P51$V DQG WKHLU UHVSHFWLYH SURWHLQ SURGXFWV 6WHLQHU DQG HDUO\WKHSRVVLELOLW\RIWR[LFRJHQRPLFVDQGSURWHRPLFVJLYLQJ QWLDODGYHUVHHIIHFWVDWORZOHYHOVRIH[SRVXUHZKLOHSRZHUIXO LQ WKH FRQWH[W RI LQWHUSUHWLQJ JHQH H[SUHVVLRQ FKDQJHVZLWK GULVNDVVHVVPHQW+RZHYHU WKHH[DPLQDWLRQRIPDQ\JHQHV DQWVPD\KHOS WRGHWHUPLQH WKHLUSRWHQWLDO WR LQGXFHDGYHUVH HGLIÀFXOWWRSUHGLFWFXUUHQWO\LQLQYLWURDVVD\V,WLVUHDVRQDEOH KHÀ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ÀFDWLRQ QHZJHQHVRUSURWHLQVWKDWKDYHHVFDSHGSUHYLRXVFRQVLGHUDWLRQ WPRVWH[FLWLQJDGYDQFHVLQGHÀQLQJWR[LFRORJLFDOPHFKDQLVPV LQWHUGLVFLSOLQDU\DQGPRUHLQWHJUDWHGWR[LFRORJ\WKDWJHQRPLFV XQGRXEWHGO\HQFRXUDJH:LWKUHVSHFWWRLQYLWURWR[LFRORJ\WKH LQWHUSUHWDWLRQRIWKHYDVWDPRXQWRIGDWDJHQHUDWHGXVLQJWKHVH VZLOOSURYLGHXVZLWKQHZLQIRUPDWLRQLQTXDOLW\DQGTXDQWLW\ SRUWXQLWLHV
REFERENCES
