Insulin Signaling, Lipoproteins and Atherosclerosis

$541,497P01FY2008HLNIH

Columbia University Health Sciences, New York NY

Investigators

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Abstract

IAmtehcehroasncislemrostiacrevapsocourlayrudnisdearsteooisd.aImnsaujloinr creasuisetaonfcme oartbthideitycealnludladrelaevthelincaduiasbeestemsa,nbyutotfhteheucnodmerplylicnagtions of diabetes. In recent collaborative studies with the Tabas and Accili laboratories, we have shown that Itmrancsrcorpiphtaiogneasl feroxmpreinssuiolin oref cCeDp3to6r a(InRd) SdeRfAic,ieinct rmeaicsedisupltaykedeofemctoivdeifieindsuLliDnLsiagndalincgr,eiansceredaseudscpeopstitb-ility to apoptosis induced by FC loading and other stimuli. Apoptotic susceptibility is related to a failure to induce IAinktot aLcDtiLvRity-/-dumrinceg trheesuEltRs isntrfeosrmsaretisopnoonfsea.dvAacnccoerdinlegslyio,nbsoncoenmtaainrrinogw itnracrnesapslaendtantuiomnbferorsmofIRapdoepfictoietinct mice Idminecacrcerreaoaspsehedadgseaigsthneanrliondsgclalterhgroeosruigsnh.eTcprhoretiscuencrvoderedrslyh.ineIngpahtiycpoInRtvhse,rswsiseromefoftohduiesnl,dpLrtDojLehRcat-v/i-semtlhoiacweteinrwsVituhLliDnpLer/reLipsDhisLetarlaenlvceIRlswdaoenrfsidceinesncy and Ifautrhtheerorsecvlearlousaiste, maceticnhganbiostmhsatlinthkeinlgevinesl uolfinthresviesstasneclewainll,mancdroaplshoaginetfhoeamlivecre.llTshteo parthopeorossacllwerilolsies,ekantod also the relationship between insulin signaling in the liver and alterations in lipoprotein metabolism. In Aim 1we Iwitllhcdoellafebcotrivaeteintosuilninvesigtingaltiengt.heInmpeacrthicaunliasrmwseawndill cdoentesremqiunencifedseocrfeinacsredasIRedsiagpnoaplintogsiasnidn lmowaecroApkhtaagcetsivity leads to increased nuclear FoxO1/3 activity, increased ER stress/CHOP induction and apoptosis. In Aim 2 Iwleesiownilallemxtaecnrdopohuarginesvivinocrsetuadsiesmanadcrfouprhthaegreaxpoloprteosthiseahnydpoathesriosmthaactodmepfelecxtivtye. inRseullaintesdigsntuadliniegs in Projects 1 and 3 will test the role of SRA and FoxOs in mediating these effects. In Aim 3 we will determine if Idinecgreradsaetdionhewpiathtiicninthseulisnecsrigentoarlyinpgaltehawdasyt.oTdhecsreeaxspeedrhimepeantisc cFomxOpl1emacetnivtityhoasnedothf uPsroinjecrte3asexdamapinoinBg the IipmropvaidcteonfehwepmatoiclecFuolxaOr i1nsoivgehrtsexipntroestshieoncaounsheespoaftidcialibpeidticanddysllipipoidperomteiainamndetiatsbovlaismcu.laTrhicsopmropjleicattimonasy.

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