The role of coagulation cascade proteases in pleural fibrosis

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，旨在促进候选人在以下领域追求独立职业的能力： 胸膜纤维化候选人来到德克萨斯大学健康科学中心泰勒作为博士后研究员，已加入教师作为生物化学助理教授，并将继续通过全面的指导和进行一个全新的，高影响力的科学项目，他过渡到独立。该计划将为胸膜纤维化的发病机制提供新的线索，胸膜纤维化每年影响数千名患者，治疗方案是侵入性的或不确定的。在本实验室报告的工作中，间皮素先前已显示通过促进局部促凝血活性和抑制胸膜腔室中的纤维蛋白溶解来促进纤维化修复。间皮细胞也可以通过间皮细胞的表型变化支持胸膜组织和不受限制的修复;间质转化（MT）。我们的初步数据支持的概念，促凝剂诱导MT。Xa因子和凝血酶在MT中的作用目前尚不清楚，将在本项目中阐明。Steven Idell博士将担任首席研究员科学发展的主要导师。Idell博士是肺和胸膜损伤凝血和纤溶领域的领导者，长期以来一直对胸膜纤维化的治疗感兴趣。他是泰勒的德克萨斯大学健康科学中心（UTHSCT）的研究副总裁，并指导了许多成功的学员。一个咨询委员会，包括华唐博士和Sreerama Shetty博士在肺纤维化领域的驻地专家和L。Vijaya Rao是凝血领域的世界知名专家，将指导申请人。他们将确保申请人实现成为一名成功的独立调查员的目标。我们的假设是Xa因子和凝血酶是MT和胸膜纤维化的重要决定因素。我们的目的是阐明凝血蛋白酶对MT的贡献以及急性胸膜损伤后胸膜腔形成和纤维化的发展。该提案的具体目的是：1）确定胸膜间皮细胞中FXa和凝血酶介导的MT的机制，2）阐明Akt和Wnt/ω-连环蛋白信号传导在PMC中FXa和凝血酶介导的MT中的作用，以及3）确定FXa和凝血酶在小鼠纤维化胸膜损伤中的作用。为了完成这项工作，将使用许多技术，包括细胞生物学、免疫学、蛋白质化学和分子生物学技术。UTHSCT的生物医学研究部门是进行这项研究项目的理想场所。强大的机构支持和热情，富有成效的咨询委员会相结合，提供了一个培育环境，使申请人能够加速他成功过渡到一个独立的调查职业生涯。 (End摘要）

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program designed to facilitate the ability of the candidate to pursue an independent career in the field of pleural fibrosis. The candidate came to The University of Texas Health Science Center at Tyler as a post-doctoral fellow, has joined the faculty as an Assistant Professor of Biochemistry and will continue his transition to independence through comprehensive mentorship and by conducting a completely novel, high impact scientific project. This program will shed new light on the pathogenesis of pleural fibrosis, which affects thousands of patients annually and for which treatment options are invasive or of uncertain benefit. In work reported by this laboratory, the mesothelium has previously been shown to promote fibrotic repair by promoting local procoagulant activity and suppressing fibrinolysis in the pleural compartment. The mesothelium can also support pleural organization and unrestricted repair via phenotypic changes of mesothelial cells; mesomesenchymal transition (MT). Our preliminary data support the concept that procoagulants induce MT. The role of factor Xa and thrombin in MT is now unknown and will be elucidated in this project. Dr. Steven Idell will serve as the primary mentor for the principal investigator's scientific development. Dr. Idell is a leader in the field of coagulation nd fibrinolysis in lung and pleural injury who has a long-standing interest in the treatment of pleura fibrosis. He is the Vice President for Research at The University of Texas Health Science Center at Tyler (UTHSCT) and has mentored numerous successful trainees. An advisory committee including Dr. Hua Tang and Dr. Sreerama Shetty resident experts in the field of lung fibrosis and Dr. L. Vijaya Rao a world renowned expert in the field of coagulation will mentor the applicant. They will ensure that the applicant achieves his objective of becoming a successful independent investigator. Our hypothesis is that factor Xa and thrombin are important determinants of MT and pleural fibrosis. Our objective is to elucidate the contribution of coagulation proteases to MT and the development of pleural loculation and fibrosis that follow acute pleural injury. The Specific Aims of the proposal are: 1) to determine the mechanism of FXa and thrombin mediated MT in pleural mesothelial cells, 2) to elucidate the role of Akt and Wnt/¿-catenin-signaling in FXa and thrombin mediated-MT in PMCs, and 3) to determine the role of FXa and thrombin in evolving fibrosing pleural injury in mice. To accomplish this work, a number of techniques, including cell biology, immunologic, protein chemistry and molecular biology techniques will be used. The Biomedical Research Department of UTHSCT is an ideal setting to conduct this research project. The combination of strong institutional support and an enthusiastic, productive advisory committee provides a nurturing environment that will enable the applicant to accelerate his successful transition to an independent investigative career. (End of Abstract)