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

通过以下途径降低低密度脂蛋白-胆固醇：使用；Q^ 死亡率和GHD引起的死亡率，但GHD仍居于首位 死亡原因：死亡和VFI？3在美国，冠心病的持久性可能是 Tacfebf:therapies‘that；)riqrease；：(HE)L-chQieste^？lt’is：是否已建立：即，L-IDL-d‘conGertti’tion is-a‘^ 由于数据表明，1毫克/分升 高密度脂蛋白-C的增加降低了冠心病风险；降低了^ Treatiesiihdt‘yyili’.ieffe‘diWjy.iele^&lt；3ri6 class’‘ibif’comfitions：：That；‘可能有。太好了；“ 治疗潜力是PHARd激动剂，在非人类灵长类动物中，它可以使HDLrG升高43-79%，并且 HiDL的主要载脂蛋白Apo/V-1增加43i%。这一应用程序；其机构由 非里马里灵长类动物中HpL-G升高的PPAR是否恶化 激动剂通过以下方式增加高密度脂蛋白-G：1)改变高密度脂蛋白的产生或分解代谢；2)改变血浆的活性 ITpasiis、脂转移蛋白和LGAT；3)调节相关基因的RNA和蛋白质表达 在高密度脂蛋白新陈代谢中。此外，PPAR6激动剂是否会升高猴子的高密度脂蛋白-C 用反义寡核苷酸抑制肝组织三磷酸腺苷结合的表达 CASS|0E，变形器A；^.iCAS‘C^ 有效地提高Hbl-C水平的PPAR6受体激动剂或其他治疗方法是合适的。其中 TURN每年可在全球范围内预防数十万人患上冠心病 世界。 科学数据表明，在增加高密度脂蛋白的选择可能会颁布 美国男性和女性死因。我们建议通过以下方式确定这些机制 其中一种新的药物，称为RPAR；Delta激动剂，可以增加猴子的高密度脂蛋白-Ghdlesterolin。因为 的身体之间的高度相似之处 研究可以提高高密度脂蛋白和预防死亡的治疗方法的发展 每年有数以千计的人死于心脏病。

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.