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

基本信息

批准号：
9973555
负责人：
Saskia Neher
金额：
$ 38.28万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9973555
关键词：
ANGPTL3 gene ANGPTL4 gene Active Sites Affect American Angiopoietins Binding Biogenesis Biological Blood Cardiovascular Diseases Cells Complex Cryoelectron Microscopy Data Drug Design Enzymes Estrogen receptor positive Excision Family Funding Genetic Grant Heart Diseases Heparin Image Individual Investigation Kinetics Knowledge Lead Lipase Lipoproteins Molecular Molecular Chaperones Molecular Weight N-terminal Peptides Plasma Production Property Proteins Reporting Request for Proposals Resistance Risk Factors Roentgen Rays Role Secretory Vesicles Serum Structure Structure-Activity Relationship Surface Therapeutic Triglycerides Variant Vesicle X-Ray Crystallography angiogenesis base cardiovascular risk factor design dimer extracellular follow-up improved inhibitor/antagonist lipoprotein lipase lipoprotein lipase inhibitor loss of function mutation nanobodies novel novel therapeutics peptidomimetics preservation prevent screening success therapeutic target trafficking wound

项目摘要

Lipoprotein lipase (LPL) is a secreted lipase and the key enzyme in clearing triglycerides from circulating lipoproteins. Because elevated plasma triglycerides are an independent risk factor for cardiovascular disease, we seek ways to enhance LPL activity, which will lower plasma triglycerides. LPL activity is downregulated by a family of macromolecular inhibitors known as angiopoietin-like (ANGPTL) proteins. This family includes the LPL inhibitors ANGPTL3, ANGPTL4, and ANGPTL8. Loss-of-function mutations in the ANGPTLs results in increased LPL activity, and decreased serum triglycerides. Our objectives in this study are to better understand how the ANGPTLs associate with LPL, and with each other, so that we can target these interactions to prevent LPL inhibition. We will achieve these objectives in three specific aims. In Aim 1, we will build on our knowledge of the mechanisms used by ANGPTL3 and ANGPTL4 to inhibit LPL to identify new therapeutics that specifically block the inhibitor-LPL interaction. In Aim 2, we will use cryo-electron microscopy to solve structures of LPL bound to its inhibitors. Finally, in Aim 3, we will study the function of inhibitors within cells, and their transport out of cells. Successful completion of these aims will provide molecular details describing how LPL and its inhibitors come together, as well as new ways to block these interactions. Because of LPL's key role in regulating plasma triglyceride levels, these discoveries hold promise for new ways to prevent cardiovascular disease.

脂蛋白脂肪酶（LPL）是一种分泌型脂肪酶，是清除循环脂蛋白中甘油三酯的关键酶。由于血浆甘油三酯升高是心血管疾病的独立危险因素，因此我们寻求增强 LPL 活性的方法，从而降低血浆甘油三酯。 LPL 活性被称为血管生成素样 (ANGPTL) 蛋白的大分子抑制剂家族下调。该家族包括 LPL 抑制剂 ANGPTL3、ANGPTL4 和 ANGPTL8。 ANGPTL 的功能丧失突变导致 LPL 活性增加，血清甘油三酯降低。我们在这项研究中的目标是更好地了解 ANGPTL 如何与 LPL 以及彼此之间关联，以便我们可以针对这些相互作用来防止 LPL 抑制。我们将通过三个具体目标来实现这些目标。在目标 1 中，我们将基于对 ANGPTL3 和 ANGPTL4 抑制 LPL 的机制的了解，以确定特异性阻断抑制剂与 LPL 相互作用的新疗法。在目标 2 中，我们将使用冷冻电子显微镜来解析与其抑制剂结合的 LPL 结构。最后，在目标 3 中，我们将研究细胞内抑制剂的功能及其向细胞外的转运。成功完成这些目标将提供描述 LPL 及其抑制剂如何结合的分子细节，以及阻止这些相互作用的新方法。由于 LPL 在调节血浆甘油三酯水平方面发挥着关键作用，这些发现有望成为预防心血管疾病的新方法。