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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

基本信息

批准号：
8018108
负责人：
Ryan Eugene Temel
金额：
$ 24.65万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018108
关键词：
ATP-Binding Cassette Transporters Address Adipose tissue Affect Agonist Antisense Oligonucleotides Apolipoprotein A-I Apolipoproteins Apolipoproteins A Catabolism Cause of Death Cercopithecus pygerythrus Cessation of life Cholesterol Cholesterol Ester Transfer Proteins Coronary heart disease Data Development Engineering Gene Expression Genes Heart Diseases Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Human Cell Line Human body Intestines LDL Cholesterol Lipoproteins Lecithin Lipase Liver Mediating Mentors Messenger RNA Metabolic Metabolism Monkeys Morbidity - disease rate Mus Muscle Organ PPAR delta Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Phospholipid Transfer Proteins Plasma Production Proteins Risk Factors Role Sampling Site Small Intestines Specificity Sterol O-Acyltransferase Testing Therapeutic Transferase United States Woman base heart disease risk hepatic lipase in vitro Assay in vivo insight lipid transfer protein lipoprotein lipase mRNA Expression men mortality nonhuman primate prevent protein expression therapy development

项目摘要

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.

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以显着降低冠心病（CHD）引起的死亡率和发病率。尽管如此，冠心病仍然是美国男性和女性死亡的主要原因。 CHD 持续存在的原因之一可能是缺乏增加高密度脂蛋白胆固醇 (HDL-C) 的治疗方法。众所周知，HDL-C 浓度是 CHD 的一个强有力的、独立的、负相关的危险因素。由于数据表明 HDL-C 每增加 1 mg/dl，CHD 风险就会降低 2-3%，因此许多制药公司正在尝试开发能够有效提高 HDL-C 水平的疗法。一类可能具有巨大治疗潜力的化合物是 PPARδ 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%。在本申请中，我建议定义 PPARδ 激动剂在非人类灵长类动物中诱导 HDL-C 升高的机制。我将通过以下方式确定 PPARδ 激动剂是否会增加 HDL-C：1) 改变 HDL 产生或分解代谢； 2)改变血浆脂肪酶、脂质转运蛋白和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 PPARδ 激动剂是否会升高经过反义寡核苷酸治疗的猴子的 HDL-C，这些反义寡核苷酸可抑制 ATP 结合盒转运蛋白 A1 (ABCA1) 的肝脏表达。我们相信，这些研究将为开发更有效的 PPARδ 激动剂或其他有效增加 HDL-C 的疗法提供见解，从而可以预防美国和世界各地每年数十万人的冠心病。