The role of coagulation cascade proteases in pleural fibrosis

凝血级联蛋白酶在胸膜纤维化中的作用

• 批准号: 8686070
• 负责人: Torry Alle Tucker
• 金额: $ 11.02万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686070
• 关键词: Acute; Address; Advisory Committees; Affect; Anesthesia procedures; Antithrombin III; Apoptosis; Area; Attenuated; Biochemistry; Biological Markers; Biomedical Research; Bleomycin; Carbon Black; Cell Survival; Cellular biology; Characteristics; Chemicals; Cicatrix; Coagulation Process; Collagen; Data; Deposition; Development; Disease; Ensure; Environment; Excision; Exhibits; Factor Xa; Faculty; Fibrin; Fibrinolysis; Fibrinolytic Agents; Fibrosis; Health Sciences; Hemorrhage; Hirudin; Hirudins; Human; Immunologics; In Vitro; Injury; Laboratories; Light; Link; Lung; Mediating; Mentors; Mentorship; Mesenchymal; Mesothelial Cell; Mesothelium; Modeling; Molecular; Molecular Biology Techniques; Mus; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Phosphorylation; Plasminogen Activator Inhibitor 1; Pleura; Pleural; Pleural Mesothelial Cell; Postdoctoral Fellow; Principal Investigator; Process; Protein Chemistry; Proteinase-Activated Receptors; Proteins; Publications; Reporting; Research; Research Personnel; Research Project Grants; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Sirolimus; Smooth Muscle Actin Staining Method; TFPI; Techniques; Texas; Thrombin; Tight Junctions; Tissues; Training Programs; Universities; Work; abstracting; base; career; cell motility; design; human FRAP1 protein; in vivo; inhibitor/antagonist; interest; mTOR Inhibitor; mouse model; new therapeutic target; novel; professor; programs; repaired; response

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)

描述（由申请人提供）：该提案描述了一个为期 5 年的培训计划，旨在提高候选人在以下领域追求独立职业的能力 胸膜纤维化。该候选人以博士后身份来到德克萨斯大学泰勒健康科学中心，并以生物化学助理教授的身份加入该学院，并将通过全面的指导和开展一项全新的、高影响力的科学项目，继续向独立过渡。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，并且治疗方案是侵入性的或疗效不确定。在该实验室报告的工作中，间皮先前已被证明可以通过促进局部促凝血活性和抑制胸膜腔内的纤维蛋白溶解来促进纤维化修复。间皮还可以通过间皮细胞的表型变化支持胸膜组织和无限制的修复；间质转化（MT）。我们的初步数据支持促凝血剂诱导 MT 的概念。 Xa 因子和凝血酶在 MT 中的作用目前尚不清楚，将在本项目中得到阐明。 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军人物，他对胸膜纤维化的治疗有着长期的兴趣。他是德克萨斯大学泰勒健康科学中心 (UTHSCT) 的研究副总裁，并指导了众多成功的学员。由肺纤维化领域常驻专家唐华博士和Sreerama Shetty博士以及凝血领域世界知名专家L. Vijaya Rao博士组成的顾问委员会将为申请人提供指导。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。我们的目标是阐明凝血蛋白酶对 MT 以及急性胸膜损伤后胸膜腔形成和纤维化的影响。该提案的具体目标是：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 PMC 中 FXa 和凝血酶介导的 MT 中 Akt 和 Wnt/¿-连环蛋白信号传导的作用，以及 3) 确定 FXa 和凝血酶在小鼠演变中的纤维化胸膜损伤中的作用。为了完成这项工作，将使用多种技术，包括细胞生物学、免疫学、蛋白质化学和分子生物学技术。 UTHSCT 生物医学研究部是开展该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，使申请人能够加速其向独立调查职业的成功过渡。 （摘要完）