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）是一种分泌的脂肪酶，也是从循环脂蛋白中清除甘油三酸酯的关键酶。由于升高的血浆甘油三酸酯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，这将降低血浆甘油三酸酯。 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。 ANGPTLS的功能丧失突变导致LPL活性增加，血清甘油三酸酯降低。我们在这项研究中的目标是更好地了解Angptls如何与LPL相关联，以便我们可以针对这些相互作用以防止LPL抑制。我们将以三个特定目标实现这些目标。在AIM 1中，我们将基于ANGPTL3和ANGPTL4使用的机制来抑制LPL以识别专门阻断抑制剂-LPL相互作用的新疗法。在AIM 2中，我们将使用冷冻电子显微镜求解与其抑制剂结合的LPL结构。最后，在AIM 3中，我们将研究细胞内抑制剂及其从细胞中传输的功能。这些目标的成功完成将提供分子细节，描述LPL及其抑制剂如何融合在一起，以及阻止这些相互作用的新方法。由于LPL在调节血浆甘油三酸酯水平方面的关键作用，这些发现对预防心血管疾病的新方法有希望。