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

• 批准号: 7250977
• 负责人: Ryan Eugene Temel
• 金额: $ 8.77万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250977
• 关键词: Address; Adipose tissue; Affect; Agonist; Antisense Oligonucleotides; Apolipoproteins; Apolipoproteins A; Catabolism; Cause of Death; Cercopithecus pygerythrus; Cessation of life; Cholesterol; Cholesterol Ester Transfer Proteins; Class; Coronary heart disease; Data; Development; Doctor of Philosophy; Elevation; Engineering; GW 501516; 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; Oligonucleotides; Organ; Other Therapy; PPAR delta; Personal Satisfaction; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Phosphatidylcholine-Sterol O-Acyltransferase; Phospholipid Transfer Proteins; Plasma; Production; Proteins; Rate; Research; Research Personnel; Risk Factors; Role; Sampling; Site; Small Intestines; Specificity; Sterol O-Acyltransferase; Testing; Therapeutic; Transferase; United States; Woman; abstracting; base; heart disease risk; hepatic lipase; in vitro Assay; in vivo; insight; lipid transfer protein; lipoprotein lipase; men; mortality; nonhuman primate; phospholipid exchange proteins; prevent; programs; protein expression; therapy development

DESCRIPTION (provided by applicant): 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 PPAR-delta 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 PPAR-delta agonists induce HDL-C elevation in non-human primates. For the mentored research phase, we will determine whether PPAR-delta 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 PPAR-delta agonists elevate HDL-C in monkeys that have been treated with antisense oligonucleotides (ASOs) that suppress hepatic expression of PPAR-delta. We feel confident that these studies will provide insights for the development of more-potent PPAR-delta 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 propose to 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 confident 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. (End of Abstract)

描述（由申请人提供）： 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 PPAR-δ 激动剂，它可以使非人类灵长类动物的 HDL-C 升高 43-79%，并使 HDL 的主要载脂蛋白 apoA-1 升高 43%。在本申请中，我们建议定义 PPAR-δ 激动剂诱导非人类灵长类动物 HDL-C 升高的机制。在指导研究阶段，我们将确定 PPAR-δ 激动剂是否通过以下方式增加 HDL-C：1) 改变 HDL 产生或分解代谢； 2)改变血浆脂肪酶、脂质转移蛋白和LCAT的活性； 3）调节参与HDL代谢的基因的mRNA和蛋白质表达。在独立研究阶段，我们建议确定 PPAR-δ 激动剂是否会升高经过反义寡核苷酸 (ASO) 治疗、抑制 PPAR-δ 肝脏表达的猴子的 HDL-C。我们相信，这些研究将为开发更有效的 PPAR-δ 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。 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，心脏病是美国男性和女性死亡的主要原因。我们建议确定一类新药物（称为 PPAR δ 激动剂）增加猴子 HDL 胆固醇的机制。由于人类和猴子的身体高度相似，我们相信这些研究将为开发可增加高密度脂蛋白并防止每年数十万人死于心脏病的疗法提供见解。 （摘要完）