Investigation of the Molecular Mechanisms of Lipoprotein Lipase Inhibitors

脂蛋白脂肪酶抑制剂的分子机制研究

• 批准号: 9102237
• 负责人: Saskia Neher
• 金额: $ 37.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102237
• 关键词: ANGPTL3 gene; ANGPTL4 gene; Address; Affect; American; Binding; Biological Markers; Blood; C-terminal; Cause of Death; Drug Design; Enzymes; Fatty acid glycerol esters; Future; Genes; Goals; Health; Heart Diseases; Human; Hypertriglyceridemia; Individual; Intervention; Investigation; Kinetics; Knowledge; Lipids; Lipoproteins; Liver; Mediating; Modeling; Molecular; Molecular Chaperones; Molecular Models; Mus; Mutation; Pharmaceutical Preparations; Plasma; Population; Protein Biochemistry; Proteins; Proteomics; Regulation; Reporting; Resistance; Risk Factors; Role; Scaffolding Protein; Serum; Site; Structure; Testing; Total Internal Reflection Fluorescent; Triglyceride Metabolism; Triglycerides; United States; Variant; Very low density lipoprotein; blood lipid; blood lipoprotein; cardiovascular disorder risk; design; enzyme replacement therapy; gain of function; gene therapy; heart disease risk; in vivo; inhibitor/antagonist; lipoprotein lipase; lipoprotein lipase inhibitor; molecular modeling; mutant; novel therapeutic intervention; novel therapeutics; population based; prevent; protein protein interaction; single molecule; therapeutic protein; tool; uptake

 DESCRIPTION (provided by applicant): Elevated serum triglycerides are associated with increased risk for cardiovascular disease. Lipoprotein lipase (LPL) is a secreted enzyme that clears lipids from the blood by hydrolyzing the triglycerides component of circulating lipoproteins. LPL has a number of macromolecular inhibitors. In human populations, known mutations in these macromolecular inhibitors result in reduced ability to inhibit LPL. As a result, LPL activity is increased and serum triglycerides are decreased. We recently discovered that one of these proteins, ANGPTL4, acts as a reversible, noncompetitive LPL inhibitor rather than an unfolding molecular chaperone as was previously believed. This new understanding of ANGPTL4 function led us to ask if other LPL inhibitors act on LPL using a similar mechanism. This proposal focuses on biochemically defining the LPL/inhibitor interaction. In Aim 1 we will define the sequence motifs and kinetic and molecular mechanisms used by these inhibitors to reduce LPL activity. In Aim 2, we will identify the features on LPL that are recognized by the inhibitors. In Aim 3 we ask why a variant of LPL has enhanced activity in vivo. To achieve these aims we will combine protein biochemistry, structural proteomics and single molecule TIRF microscopy. Successful completion of these aims will provide a precise molecular understanding of the mechanism of LPL activity and regulation. Because of LPL's key role in human triglyceride metabolism, these discoveries hold promise for developing new therapies for hypertriglyceridemia.

 描述（由申请人提供）：血清甘油三酯升高与心血管疾病风险增加相关。脂蛋白脂肪酶 (LPL) 是一种分泌酶，通过水解循环脂蛋白的甘油三酯成分来清除血液中的脂质。 LPL具有多种大分子抑制剂。在人类中，这些大分子抑制剂的已知突变会导致抑制 LPL 的能力降低。因此， LPL 活性增加，血清甘油三酯降低。我们最近发现其中一种蛋白质 ANGPTL4 充当可逆的、非竞争性 LPL 抑制剂，而不是像之前认为的那样是一种展开分子伴侣。对 ANGPTL4 功能的这种新认识使我们想知道其他 LPL 抑制剂是否使用类似的机制作用于 LPL。该提案的重点是从生化角度定义 LPL/抑制剂相互作用。在目标 1 中，我们将定义这些抑制剂用于降低 LPL 活性的序列基序以及动力学和分子机制。在目标 2 中，我们将识别 LPL 上被抑制剂识别的特征。在目标 3 中，我们询问为什么 LPL 的变体具有增强的体内活性。为了实现这些目标，我们将蛋白质生物化学、结构蛋白质组学和单分子 TIRF 显微镜相结合。成功完成这些目标将为 LPL 活性和调节机制提供精确的分子理解。由于 LPL 在人类甘油三酯代谢中的关键作用，这些发现有望开发出治疗高甘油三酯血症的新疗法。