Structure-Function and Roles of Protease-Activated Receptors

蛋白酶激活受体的结构-功能和作用

• 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
• 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

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.

项目摘要/摘要 我的实验室试图了解蛋白酶，通过切割其他的蛋白酶，关键的生物调节剂 分子，控制细胞行为以及这种蛋白酶信号在胚胎发育中的作用，成人 生理和疾病。我们发现并表征了蛋白酶激活的受体（PARS）。这些 分子跨越细胞膜，感知细胞外蛋白酶活性，并将此信息传输到其中 触发响应的单元格。蛋白酶通过在特定位点上切割Pars来揭示AS的蛋白酶信号传导 激活剂是受体的一部分，但直到被蛋白酶发现为止。这项工作揭示了如何 凝血酶是一种钥匙血凝结酶，激活血小板，塞子破裂血管的小细胞 停止流血或患病的动脉引起心脏病发作和中风。这些发现导致了一种新类型 抗血栓药物（vorapaxar/zontivity）。这项工作还发现了蛋白酶信号的意外角色 在内皮，平滑肌和上皮细胞，神经元和其他细胞类型中，其中许多仍保留 未探索。我们试图以这个基础为基础，以更好地理解PARS如何发挥信号 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在通过凝血酶切割时如何活跃的结构基础，将信息传输到整个 细胞膜，并选择将夫妇夫妇置于活化受体内部的信号蛋白和 将信息传输到单元的内部。 2）PAR信号在造型中的作用在组中的作用， 维持胚胎和成人的血管。 3）蛋白酶信号在调节 上皮的行为，有组织的细胞床单，这些细胞分离隔室并起着关键作用 心脏，肺，肾脏，肠道，肝脏，内分泌和外分泌腺，大脑，皮肤和皮肤的形成和功能 其他器官。在我们的研究中的成功将提高我们对Pars本身和大型的理解 它们所属的受体家族（G蛋白偶联受体 - 关键调节剂和药物靶标）。会 还可以提高我们对控制血管形成和功能的机制的理解 和上皮，潜在的广泛影响。