Signaling Pathways Regulating Serum Response Factor in Pulmonary Fibrosis

描述（由申请人提供）： 本提案概述了一个为期5年的培训计划，以发展学术肺的职业生涯。主要研究者（PI）已完成芝加哥大学内科住院医师培训，随后获得芝加哥大学肺部和重症监护医学研究金。他现在是芝加哥大学肺部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。该项目将促进细胞信号传导在人类纤维化疾病（如肺纤维化和闭塞性细支气管炎）基本机制研究中的应用。Nickolai Dulin博士将指导主要研究者的科学发展。他是细胞信号传导领域的知名研究者，也是一位杰出的导师，致力于将PI发展成为独立的临床医生-科学家。Julian Solway博士是一位杰出的医生-研究者，他成功地培训了许多临床医生-科学家，他将担任共同导师。他将提供学术和科学职业发展方面的专业知识。此外，在细胞信号，肺生理学和分子生物学方面有成就的科学家的咨询委员会将有助于科学和职业发展。研究重点将是血清反应因子（SRF）在肺纤维化背景下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TGF-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伊洛前列素减弱鼠模型中肺纤维化的发展。因此，总体假设是TGF-β通过激活血清应答因子刺激肌成纤维细胞分化，并且TGF-β诱导的肌成纤维细胞分化可以通过靶向细胞培养物和体内的SRF活性来抑制。相关性（参见说明）：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。这些信号通路的鉴定可能导致这种进行性致命疾病的新药治疗的开发。(End摘要）

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)