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

PPARδ 激动剂诱导非人灵长类动物 HDL 升高的机制

• 批准号: 7760739
• 负责人: Ryan Eugene Temel
• 金额: $ 24.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760739
• 关键词: Agonist; Apolipoproteins; Binding; CETP gene; Catabolism; Cause of Death; Cercopithecus pygerythrus; Cessation of life; Cholesterol; Cholesterol Ester Transfer Proteins; Coronary heart disease; Data; Development; Disease; Genes; Heart Diseases; Heparin; Hepatic; High Density Lipoproteins; Isotopes; Lead; Lecithin; Lipase; Mediating; Metabolism; Monkeys; PPAR delta; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Plasma; Primates; Production; Proteins; Reporting; Rhea; Risk; Sampling; Testing; Therapeutic; Transferase; United States; Woman; absorption; cholesterol absorption; density; hepatic lipase; lipid transfer protein; lipoprotein lipase; men; nonhuman primate; prevent; protein expression; reverse cholesterol transport

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.

通过使用降低LDL-胆固醇; GHD引起的死亡率和n（16 rb）<3，但GHD仍是引起GHD的主要原因， 在美国，冠心病持续存在的原因可能是： tacfebf：therapies'that;）riqrease;：（HE）L-chQieste^<$lt'is：wiBll'established：that.，我-我-我！是-a '^ 由于数据表明，1 mg/dl HDL升高。C降低CHD风险;通过 治疗'yyili'. ieffe'diWjy.iele^ <3ri6 class''ibif' Comfounds：：that third 'may have.great;” 具有治疗潜力的是PHARd激动剂，其在非人灵长类动物中可使HDLrG升高43-79%， hiDL的主要载脂蛋白apo/V-1的表达降低了43%。在本申请中，提供了通过以下方式实现的机制： 在非利马里灵长类动物中，PPARS是否升高， 激动剂通过以下方式增加HDL-G：1）改变HDL产生或催化剂; 2）改变血浆 ITPasiis、脂质转运蛋白和LGAT; 3）调节相关基因的RNA和蛋白表达 高密度脂蛋白代谢。此外，我还想确定PPAR 6激动剂是否会升高猴的HDL-C。 用反义寡核苷酸抑制肝脏ATP结合的表达， 卡斯|0e，traps pdrter A;^ .iCAS'C^ 开发强效PPAR 6激动剂或其他有效增加HbL-C的治疗。这 在Onlted Statistss和大约2000年， 世界 科学数据表明，高密度脂蛋白胆固醇的增加可能会导致 美国男性和女性的死亡原因。我们建议通过以下方式确定机制： 一种叫做RPAR的新药; δ激动剂，可以增加猴子的HDL-胆固醇。因为 的高cjegr^的相似性之间的机构， 研究可以增加HDL和预防死亡的治疗方法的发展 每年有成千上万的人死于心脏病。