The role of coagulation cascade proteases in pleural fibrosis

描述(由申请人提供)：这份建议书描述了一项为期5年的培训计划，旨在促进候选人在以下领域寻求独立职业生涯的能力 胸膜纤维化。这位候选人以博士后身份来到位于泰勒的德克萨斯大学健康科学中心，作为生物化学助理教授加入教职，并将通过全面的指导和实施一个全新的、高影响力的科学项目来继续他向独立的过渡。该计划将为胸膜纤维化的发病机制提供新的线索，这种疾病每年影响数千名患者，其治疗选择是侵入性的或受益不确定的。在该实验室报告的工作中，先前已证明间皮细胞通过促进局部促凝血活性和抑制胸膜腔内的纤溶作用来促进纤维化修复。间皮细胞还可以通过间皮细胞表型的改变支持胸膜组织和无限制的修复；间充质转化(MT)。我们的初步数据支持促凝血剂诱导MT的概念。凝血因子Xa和凝血酶在MT中的作用目前尚不清楚，将在本项目中阐明。史蒂文·伊德尔博士将担任首席研究员科学发展的主要导师。伊德尔博士是肺和胸膜损伤的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。他是德克萨斯大学泰勒健康科学中心(UTHSCT)负责研究的副总裁，曾指导过许多成功的学员。由唐华博士和Sreerama Shetty博士组成的咨询委员会将指导申请者，他们是肺纤维化领域的常驻专家，以及世界知名的凝血领域专家L.Vijaya Rao博士。他们将确保申请人实现其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酶在MT中的作用以及急性胸膜损伤后胸膜形成和纤维化的发展。本研究的具体目的是：1)确定FXA和凝血酶介导的胸膜间皮细胞MT的作用机制；2)阐明Akt和Wnt/β-catenin信号在FXA和凝血酶介导的PMCs中的作用；3)确定FXA和凝血酶在小鼠纤维化胸膜损伤形成中的作用。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的生物医学研究部是开展这一研究项目的理想场所。强有力的机构支持和热情、富有成效的咨询委员会相结合，提供了一个培育环境，使申请人能够加快向独立调查职业的成功过渡。(摘要结束)

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)