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-胆固醇已被证明显著降低了 冠心病(CHD)造成的死亡率和发病率。尽管如此，CHD仍然是领先的 美国男性和女性的死因。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(高密度脂蛋白胆固醇)的治疗方法。众所周知，高密度脂蛋白-C浓度是一种 冠心病的强烈、独立、负相关的危险因素。因为数据显示1毫克/分升 增加高密度脂蛋白胆固醇可降低2-3%的冠心病风险，许多制药公司正在尝试开发 有效提高高密度脂蛋白胆固醇水平的疗法。一类化合物可能具有很好的 治疗潜力是PPAR6激动剂，它在非人类灵长类动物中可以使高密度脂蛋白-C升高43-79%， 载脂蛋白A-L，高密度脂蛋白的主要载脂蛋白，增加了43%。在本应用程序中，我们建议定义机制 通过PPAR6激动剂在非人类灵长类动物中诱导高密度脂蛋白-C升高。用于指导研究 阶段，我们将确定PPAR5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 高密度脂蛋白代谢相关基因的mRNA和蛋白表达。对于独立研究阶段， 我们建议确定PPAR6激动剂是否会升高接受了以下治疗的猴子的高密度脂蛋白胆固醇 抑制肝脏PPAR6表达的反义寡核苷酸(ASO)。我们确信这些都是 研究将为开发更有效的PPAR6激动剂或其他治疗方法提供见解 有效地提高高密度脂蛋白-C，这反过来又可以每年预防数十万人的冠心病 在美国和世界各地。 科学数据表明，增加高密度脂蛋白胆固醇可能会降低心脏病的风险，这是 美国男性和女性的死因。我们建议通过以下方式来确定这些机制 一种名为PPAR Delta激动剂的新型药物会增加猴子体内的高密度脂蛋白-胆固醇。因为 由于人类和猴子的身体高度相似，我们确信这些 研究将为提高高密度脂蛋白和预防死亡的治疗方法的开发提供见解 每年有数十万人死于心脏病。

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 PPAR6 agonists, which in non-human primates can elevate HDL-C by 43-79% and apoA-l, the major apolipoprotein of HDL, by 43%. In this application, we propose to define the mechanisms by which PPAR6 agonists induce HDL-C elevation in non-human primates. For the mentored research phase, we will determine whether PPAR5 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. For the independent research phase, we propose to determine whether PPAR6 agonists elevate HDL-C in monkeys that have been treated with antisense oligonucleotides (ASOs) that suppress hepatic expression of PPAR6. We feel confidant that these studies will provide insights for the development of more-potent PPAR6 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. Scientific data indicates that increasing HDL cholesterol may decrease the risk of heart disease, the leading cause of death for men and women in the United States. We proposeto determine the mechanisms by which a new class of drugs, known as PPAR delta agonists, increase HDL-cholesterol in monkeys. Because of the high degree of similarity between the bodies of humans and monkeys, we feel confidant that these studies will provide insights for the development of therapies that could increase HDL and prevent the deaths of hundreds of thousands of people each year from heart disease.