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.

项目总结/摘要 我的实验室试图了解蛋白酶，一种通过切割其他蛋白质来发挥作用的关键生物调节剂， 分子，支配细胞行为和这种蛋白酶信号传导在胚胎发育，成年 生理学和疾病。我们发现并表征了蛋白酶激活受体（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递到细胞内 细胞来触发反应蛋白酶通过在特定位点切割PAR来触发信号传导， 作为受体的一部分但隐藏直到被蛋白酶发现的激活剂。这项工作揭示了 凝血酶是一种关键的凝血酶，它能激活血小板，即堵塞破裂血管的小细胞 阻止出血或动脉病变导致心脏病和中风。这些发现导致了一种新的类型 抗血栓药物（vorapaxar/Zontivity）。这项工作还发现了蛋白酶信号传导的意想不到的作用 在内皮细胞、平滑肌细胞和上皮细胞、神经元和其他细胞类型中，其中许多仍然大量存在， 未开发的我们试图在此基础上更好地理解PAR如何作为信号传导发挥作用 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方面： PAR 1在凝血酶切割后如何变得有活性的结构基础，通过凝血酶传递信息。 细胞膜，并选择信号蛋白，耦合到内部的激活受体， 将信息传递到细胞内部。2)血管壁中PAR信号在血管内皮细胞增殖和分化中的作用 维持胚胎和成人的血管。3)蛋白酶信号在调节细胞凋亡中的作用 上皮细胞的行为，有组织的细胞片，分隔区室，并发挥关键作用， 心脏、肺、肾、肠、肝、内分泌和外分泌腺、脑、皮肤和 其他器官。我们的研究的成功将促进我们对PAR本身和大的 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点）。它将 也促进了我们对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。