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-胆固醇已被证明能显著降低由冠心病(CHD)引起的死亡率和发病率。然而，在美国，冠心病仍然是导致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提高高密度脂蛋白-胆固醇(HDLC)的治疗方法。众所周知，高密度脂蛋白胆固醇浓度是冠心病的一个强大的、独立的、负相关的危险因素。由于有数据表明，高密度脂蛋白胆固醇每增加1毫克/分升就能降低2-3%的冠心病风险，因此许多制药公司都在尝试开发能有效提高高密度脂蛋白胆固醇水平的疗法。一类可能具有巨大治疗潜力的化合物是PPARDelta激动剂，在非人类灵长类动物中，它可以使高密度脂蛋白-C升高43-79%，高密度脂蛋白的主要载脂蛋白apoA-I提高43%。在这个应用中，我建议定义PPARDelta激动剂在非人类灵长类动物中诱导高密度脂蛋白-C升高的机制。我将确定PPARDelta激动剂是否通过以下方式增加高密度脂蛋白胆固醇：1)改变高密度脂蛋白的产生或分解代谢；2)改变血浆脂肪酶、脂转移蛋白和LCAT的活性；3)调节参与高密度脂蛋白代谢的基因的mRNA和蛋白质表达。此外，我建议确定PPARDelta激动剂是否提高了用反义寡核苷酸治疗的猴子的高密度脂蛋白-C，这些反义寡核苷酸抑制了肝脏ATP结合盒转运体A1(ABCA1)的表达。我们相信，这些研究将为开发更有效的PPARDelta激动剂或其他有效提高高密度脂蛋白-C的疗法提供洞察力，这反过来又可以在美国和世界各地每年预防数十万人患上冠心病。

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.