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

通过使用他汀类药物降低LDL-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，CHD仍然是美国男性和女性的主要死亡原因。 CHD持续存在的一个原因可能是缺乏增加HDL-胆固醇（HDL-C）的治疗。 HDL-C浓度是CHD的一个强的、独立的、负相关的危险因素。 由于数据表明HDL-C增加1 mg/dl可使CHD风险降低2- 3%，因此许多制药公司正试图开发有效提高HDL-C水平的疗法。 可能具有巨大治疗潜力的一类化合物是PPARdelta激动剂，其在非人灵长类动物中可使HDL-C升高43-79%，并使apoA-I（HDL的主要载脂蛋白）升高43%。 在这个应用中，我建议定义的机制，通过哪些PPARdelta激动剂诱导HDL-C在非人灵长类动物的升高。 我将确定PPARdelta激动剂是否通过以下方式增加HDL-C：1）改变HDL产生或催化; 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和蛋白质表达。 此外，我建议，以确定是否PPARdelta激动剂升高HDL-C的猴子已经与反义寡核苷酸，抑制肝脏表达的ATP结合盒转运蛋白A1（ABCA 1）。 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，这反过来又可以预防美国和世界各地每年数十万人的CHD。

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.