Structure-Function and Roles of Protease-Activated Receptors

蛋白酶激活受体的结构-功能和作用

基本信息

批准号：
9242892
负责人：
SHAUN R. COUGHLIN
金额：
$ 39.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-14 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242892
关键词：
Adult Area Arteries Behavior Biological Biology Blood Platelets Blood Vessels Blood coagulation Brain Cell membrane Cells Cleaved cell Disease Drug Targeting Embryo Embryonic Development Endocrine Glands Endothelial Cells Epithelial Epithelial Cells Epithelium Exocrine Glands F2R gene Family Foundations Future G-Protein-Coupled Receptors Hemorrhage Individual Laboratories Liver Maintenance Myocardial Infarction Neurons Organ Patient Selection Peptide Hydrolases Pharmaceutical Preparations Physiology Play Proteinase-Activated Receptors Receptor Signaling Renal function Respiratory physiology Role Signal Transduction Signaling Protein Site Skin Smooth Muscle Myocytes Stroke Structure Thrombin Tissues Ursidae Family Work cell behavior cell type clotting enzyme drug development extracellular heart function receptor receptor function response success

项目摘要

Project Summary/Abstract My laboratory seeks to understand how proteases, key biological regulators that act by cleaving other molecules, govern cellular behaviors and the roles of such protease signaling in embryonic development, adult physiology and disease. We discovered and characterized Protease-Activated Receptors (PARs). These molecules span the cell membrane, sense extracellular protease activity and transmit this information inside the cell to trigger responses. Proteases trigger signaling by cleaving PARs at a specific site to unmask an activator that is part of the receptor but hidden until uncovered by the protease. This work revealed how thrombin, a key blood clotting enzyme, activates blood platelets, the small cells that plug broken blood vessels to stop bleeding or diseased arteries to cause heart attacks and strokes. These discoveries led to a new type of antithrombotic drug (vorapaxar/Zontivity). The work also uncovered unexpected roles for protease signaling in endothelial, smooth muscle, and epithelial cells, neurons and other cell types, many of which remain largely unexplored. We seek to build on this foundation to better understand how PARs function as signaling machines and their roles in normal biology and disease. Our future work will focus on three important areas: 1) The structural basis of how PAR1 becomes active upon cleavage by thrombin, transmits information across the cell membrane, and chooses the signaling proteins that couple to the inside of the activated receptor and transmit information to the cell's interior. 2) The role of PAR signaling in the vessel wall in the formation and maintenance of blood vessels in the embryo and adult. 3) The role of protease signaling in regulating the behavior of epithelia, organized sheets of cells that separate compartments and play critical roles for the formation and function of the heart, lungs, kidneys, gut, liver, endocrine and exocrine glands, brain, skin and other organs. Success in our studies will advance our understanding of PARs themselves and of the large family of receptors to which they belong (G protein-coupled receptors - key regulators and drug targets). It will also advance our understanding of the mechanisms that govern the formation and function of blood vessels and epithelia, with potential broad impact.

项目概要/摘要我的实验室致力于了解蛋白酶（通过裂解其他物质发挥作用的关键生物调节剂）如何发挥作用。分子，控制细胞行为以及此类蛋白酶信号在胚胎发育、成人中的作用生理学和疾病。我们发现并表征了蛋白酶激活受体 (PAR)。这些分子跨越细胞膜，感知细胞外蛋白酶活性并将此信息传递到内部细胞触发反应。蛋白酶通过在特定位点切割 PAR 来触发信号传导，从而揭开激活剂是受体的一部分，但在被蛋白酶发现之前是隐藏的。这项工作揭示了如何凝血酶是一种关键的凝血酶，可激活血小板，即堵塞破裂血管的小细胞止血或阻止病变动脉导致心脏病发作和中风。这些发现催生了一种新的类型抗血栓药物（vorapaxar/Zontivity）。这项工作还揭示了蛋白酶信号传导的意想不到的作用在内皮细胞、平滑肌细胞、上皮细胞、神经元和其他细胞类型中，其中许多细胞很大程度上仍然存在未经探索。我们寻求在此基础上更好地理解 PAR 如何发挥信号作用机器及其在正常生物学和疾病中的作用。我们未来的工作将集中在三个重要领域：1） PAR1 在被凝血酶裂解后变得活跃并跨过细胞传递信息的结构基础细胞膜，并选择与激活受体内部偶联的信号蛋白将信息传递到细胞内部。 2) PAR信号在血管壁形成和形成中的作用维持胚胎和成人的血管。 3）蛋白酶信号传导在调节中的作用上皮细胞的行为，有组织的细胞片，将隔室分隔开来，并在心脏、肺、肾脏、肠道、肝脏、内分泌和外分泌腺、大脑、皮肤和其他器官。我们研究的成功将增进我们对 PAR 本身和大型它们所属的受体家族（G 蛋白偶联受体 - 关键调节因子和药物靶标）。它将也增进了我们对控制血管形成和功能的机制的理解和上皮细胞，具有潜在的广泛影响。