Structure-Function and Roles of Protease-Activated Receptors

项目摘要/摘要 我的实验室试图了解蛋白酶，一种关键的生物调节因子，通过切割其他 分子，控制细胞行为和这种蛋白酶信号在胚胎发育中的作用，成体 生理学和疾病。我们发现并鉴定了蛋白酶激活受体(PARs)。这些 分子跨越细胞膜，感知细胞外的蛋白酶活性，并将这一信息传递到内部 触发响应的单元格。蛋白水解酶通过在特定位置切割PARs来触发信号传递，从而揭开 激活剂是受体的一部分，但在被蛋白酶发现之前一直隐藏着。这项工作揭示了 凝血酶是一种关键的血液凝固酶，它能激活血小板，这种小细胞可以堵塞破裂的血管 止血止血或动脉病变以引起心脏病发作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水解酶信号的意想不到的作用 在内皮细胞、平滑肌细胞、上皮细胞、神经元和其他类型的细胞中，许多细胞基本上 未被开发的。我们试图在此基础上更好地理解PAR作为信号的功能 机器及其在正常生物学和疾病中的作用。我们今后的工作将集中在三个重要方面：1) PAR1在被凝血酶切割后如何变得活跃的结构基础，通过 细胞膜，并选择偶联到激活的受体内部的信号蛋白和 将信息传输到细胞内部。2)PAR信号在血管壁中的作用 胚胎和成体血管的维持。3)蛋白水解酶信号在调节细胞周期中的作用。 上皮细胞的行为，是一种有组织的细胞片，用于分隔隔室，并在 心、肺、肾、肠道、肝脏、内分泌腺和外分泌腺、脑、皮肤和 其他器官。我们研究的成功将促进我们对PAR本身和更广泛的理解 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)。会的 也促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。

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.