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

通过使用他汀类药物降低低密度脂蛋白胆固醇已被证明可显著降低冠心病（CHD）引起的死亡率和发病率。然而，冠心病仍然是美国男性和女性死亡的主要原因。冠心病持续存在的一个原因可能是缺乏增加高密度脂蛋白胆固醇（HDL-C）的治疗方法。HDL-C浓度是冠心病的一个强大的、独立的、负相关的危险因素。由于数据表明HDL-C每增加1毫克/分升可降低2-3%的冠心病风险，许多制药公司正试图开发有效提高HDL-C水平的疗法。一类可能具有巨大治疗潜力的化合物是PPARdelta激动剂，它可以使非人类灵长类动物的HDL- c升高43-79%，使HDL的主要载脂蛋白apoA-I升高43%。在这个应用中，我建议定义PPARdelta激动剂诱导非人类灵长类动物HDL-C升高的机制。我将确定ppar受体激动剂是否通过以下方式增加HDL- c: 1)改变HDL的生成或分解代谢；2)改变血浆脂肪酶、脂质转移蛋白和LCAT的活性；3)调节HDL代谢相关基因的mRNA和蛋白表达。此外，我建议确定PPARdelta激动剂是否会升高猴子体内的HDL-C，这些猴子被反义寡核苷酸抑制ATP结合盒转运体A1 （ABCA1）的肝脏表达。我们相信，这些研究将为开发更有效的PPARdelta激动剂或其他有效增加HDL-C的疗法提供见解，从而每年在美国和世界各地预防成千上万的人患冠心病。

Reduction of LDL-cholesterol through the use of statins has been shown to significantly decrease the rate of mortality and morbidity caused by coronary heart disease (CHD). Nevertheless, CHD remains the leading cause of death for men and women in the United States. One reason for the persistence of CHD may be the lack of therapies that increase HDL-cholesterol (HDL-C). It is well established that HDL-C concentration is a strong, independent, inversely related risk factor for CHD. Because of data indicating that a 1 mg/dl increase in HDL-C decreases CHD risk by 2-3%, many pharmaceutical companies are attempting to develop therapies that will effectively elevate HDL-C levels. One class of compounds that may have great therapeutic potential are PPARdelta agonists, which in non-human primates can elevate HDL-C by 43-79% and apoA-I, the major apolipoprotein of HDL, by 43%. In this application, I propose to define the mechanisms by which PPARdelta agonists induce HDL-C elevation in non-human primates. I will determine whether PPARdelta agonists increase HDL-C by: 1) altering HDL production or catabolism; 2)changing the activity of plasma lipases, lipid transfer proteins, and LCAT; 3)modulating the mRNA and protein expression of genes involved in HDL metabolism. In addition, I propose to determine whether PPARdelta agonists elevate HDL-C in monkeys that have been treated with antisense oligonucleotides that suppress hepatic expression of ATP binding cassette transporter A1 (ABCA1). We feel confidant that these studies will provide insights for the development of more-potent PPARdelta agonists or other therapies that effectively increase HDL-C, which in turn could prevent CHD in hundreds of thousands of people each year in the United States and around the world.