Signaling Pathways Regulating Serum Response Factor in Pulmonary Fibrosis

描述(由申请人提供)： 这份提案概述了一项为期5年的培训计划，以发展学术肺科的职业生涯。首席研究员(PI)在芝加哥大学完成了内科住院医师资格，随后在芝加哥大学获得了肺部和危重护理医学研究员学位。他现在是芝加哥大学肺科和重症监护科的讲师(2008年7月1日生效)。他将通过一个独特的细胞信号训练计划来扩展他的科学技能。这项计划将促进对细胞信号在纤维化人类疾病基本机制研究中的应用，如肺纤维化和闭塞性细支气管炎。Nickolai Dlin博士将指导首席研究员的科学发展。他是细胞信号方面的知名研究员和杰出的导师，致力于将PI发展成为一名独立的临床科学家。朱利安·索尔韦博士是一位杰出的医生兼研究员，他成功地培养了许多临床医生和科学家，他将担任联合导师。他将提供学术和科学职业发展方面的专业知识。此外，一个由细胞信号、肺生理学和分子生物学领域的资深科学家组成的咨询委员会将为科学和职业发展做出贡献。研究重点将集中在血清反应因子(SRF)在肺纤维化形成过程中介导肌成纤维细胞分化中的作用。PIS初步数据显示：1)促纤维化细胞因子--转化生长因子-β诱导的肌成纤维细胞分化需要SRF，2)PKA激活剂可能通过抑制SRF抑制肌成纤维细胞分化，3)稳定的前列环素激动剂iloprost可减轻小鼠肺纤维化的发展。因此，总体的假设是，转化生长因子-β通过激活血清反应因子促进肌成纤维细胞的分化，而在细胞培养和体内靶向SRF活性可以抑制转化生长因子-β诱导的肌成纤维细胞分化。相关性(见说明)：我的长期目标是了解肺纤维化发病机制的分子机制，重点是肌成纤维细胞分化。这些信号通路的识别可能会导致这种进行性致命疾病的新药治疗的发展。(摘要结束)

DESCRIPTION (provided by applicant): A 5 year training program for the development of a career in academic pulmonary is outlined in this proposal. The principal investigator (PI) has completed residency in internal medicine at the University of Chicago followed by a fellowship in pulmonary and critical care medicine at the University of Chicago. He is now an Instructor in the Section of Pulmonary and Critical Care, University of Chicago (effective July 1, 2008). He will expand upon his scientific skills through a unique program of training in cellular signaling. This program will promote command of the application of cellular signaling to the study of basic mechanisms of fibrotic human diseases, such as pulmonary fibrosis and bronchiolitis obliterans. Dr. Nickolai Dulin will mentor the principal investigator's scientific development. He is a well-established investigator in cell signaling and an outstanding mentor who is committed to the development of the PI into an independent clinician-scientist. Dr. Julian Solway, an outstanding physician-investigator who has successfully trained many clinician-scientists will serve as the Co-Mentor. He will provide expertise in academic and scientific career development. In addition, an advisory committee of accomplished scientists in cellular signaling, pulmonary physiology, and molecular biology will contribute to the scientific and career development. The research focus will be on the role of serum response factor (SRF) in mediating myofibroblast differentiation in the setting of pulmonary fibrosis. The Pis preliminary data shows that 1) SRF is required for myofibroblast differentiation induced by the profibrotic cytokine, TGF-beta, 2) that activators of PKA inhibits myofibroblast differentiation likely via inhibition of SRF, and 3) the stable prostacyclin agonist, iloprost, attenuates the development of pulmonary fibrosis in a murine model. Thus, the overall hypothesis is that TGF-beta stimulates myofibroblast differentiation through activation of serum response factor, and that TGF- beta-induced myofibroblast differentiation can be inhibited by targeting SRF activity both in cell culture and in vivo. RELEVANCE (See instructions): My long-term objective is to understand the molecular mechanisms underlying the pathogenesis of pulmonary fibrosis, focusing on myofibroblast differentiation. Identification of these signaling pathways may lead to the development of new drug treatments for this progressive, fatal disease. (End of Abstract)