Mechanisms For PPARdelta Agonist-Induced Elevation of HDL in Non-Human Primates

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RedudionjofLDL-cholesterol through the: use;q^ mprtality and n(i6rb)<3ity caused by GO ro disease (GHD), Nevertheless, GHD remains the leading caijse of: death fbrnnen and vfi¿3men in the United Stat^, OneireasQfi for the persistence of CHD may be the tacfebf:therapies'that;)riqrease;:(HE)L-chQieste^ ¿lt'is:wiBll'established:that.,l-iDL-d'conGertti¿!tion is-a'^ stripng,ihdeipendentjnver^ely^^^m^ Because of data Indicating that a 1 mg/dl increase in HDL.-C decreases CHD risk; by ^^^^ therapiesiihdt'yyili'.ieffe'diWjy.iele^ <3ri6 class''ibif'Comfiounds::that;'may have.great;" therapeutic potential are PHARd agonists, which in non'human primates can elevate HDLrG by 43-79% and apo/V-1, themajor apolipoprotein of HiDL, by 43i%. Irt this applicatiprv, j prpposetpdeflne;the mechanisms by which PPARftagtjhlstsiriGiuceHpL-G elevation in non-liymari primates, twill deteriTiine whether PPARS agonists increase HDL-G by: 1) altering HDL production or catabolism; 2) changing the activity of plasma ITpasiis, lipid transfer proteins, and LGAT; 3) mpdolating themRNA and protein expression of genes involved in HDL metabolism. In addition, I pnoppse to determine whether PPAR6 agonists elevate HDL-C in monkeys that have Ibeen treated with antisense oligonudeptides that suppress hepatic expression of ATP binding cass|0e,trarispdrter A;^ .iCAS'C^ deN^loprhisfit of rnbre-potent PPAR6 agbnlsts or other therapiesthateffeetiveiy increase HbL-C. which in turn could prevent CHD in hundreds of thousands pf people each year in the Onlted Statisss and around the world. Scientific data indicates that inGreasing HDL choiasterol may decree cause of death for men arid women in the United States. We propose to determine the mechanisms by which a new class of drugs, known as RPAR;delta agonists, increase HDL-Ghdlesterolin monkeys. Because of the high cjegr^ of similality between the bodies of studies \yillproyideinsighlsf6i'the development of therapieis that could increase HDL and prevent the deaths of iiuhdreds of thousands of ;people each year from heart disease.