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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.

项目总结/文摘