Abstract

IAmtehcehroasncislemrostiacrevapsocourlayrudnisdearsteooisd.
aIm nsaujloinr 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 1 we 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL087123-03
Application #
7883468
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$541,497
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032

  Publications

Molusky, Matthew M; Hsieh, Joanne; Lee, Samuel X et al. (2018) Metformin and AMP Kinase Activation Increase Expression of the Sterol Transporters ABCG5/8 (ATP-Binding Cassette Transporter G5/G8) With Potential Antiatherogenic Consequences. Arterioscler Thromb Vasc Biol 38:1493-1503
Cai, Bishuang; Kasikara, Canan; Doran, Amanda C et al. (2018) MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci Signal 11:
Accili, Domenico (2018) Insulin Action Research and the Future of Diabetes Treatment: The 2017 Banting Medal for Scientific Achievement Lecture. Diabetes 67:1701-1709
Haeusler, Rebecca A; McGraw, Timothy E; Accili, Domenico (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31-44
Kraakman, Michael J; Liu, Qiongming; Postigo-Fernandez, Jorge et al. (2018) PPAR? deacetylation dissociates thiazolidinedione's metabolic benefits from its adverse effects. J Clin Invest 128:2600-2612
Ghorpade, Devram S; Ozcan, Lale; Zheng, Ze et al. (2018) Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature 555:673-677
Fredman, Gabrielle; Tabas, Ira (2017) Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. Am J Pathol 187:1211-1221
Doran, Amanda C; Ozcan, Lale; Cai, Bishuang et al. (2017) CAMKII? suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J Clin Invest 127:4075-4089
Tabas, Ira; Lichtman, Andrew H (2017) Monocyte-Macrophages and T Cells in Atherosclerosis. Immunity 47:621-634
Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2017) MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 127:564-568

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