Signaling Pathways Regulating Serum Response Factor in Pulmonary Fibrosis

调节肺纤维化血清反应因子的信号通路

基本信息

批准号：
8243539
负责人：
NATHAN K SANDBO
金额：
$ 12.42万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-09 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8243539
关键词：
Actins Adenoviruses Advisory Committees Agonist Alveolar Animal Model Animals Area Attenuated Biochemical Blood Vessels Bronchiolitis Obliterans Cell Culture Techniques Chicago Collagen Commit Contractile Proteins Critical Care Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Epithelial Cells Event Fellowship Fibroblasts Fibrosis Forskolin Gene Delivery Gene Expression Gene Expression Profile Goals Growth Factor Hamman-Rich syndrome Histologic Human Iloprost Inflammation Inflammatory Injury Instruction Internal Medicine Intervention Investigation Lead Lung Measurement Mechanics Mediating Mediator of activation protein Medicine Mentors Modeling Molecular Molecular Biology Mus Myofibroblast Pathogenesis Patients Pharmaceutical Preparations Phenotype Phosphorylation Physicians Physiological Physiology Play Principal Investigator Program Development Prostaglandins I Publishing Pulmonary Fibrosis Regulation Reporting Research Research Personnel Residencies Role Scientist Series Serine Serum Serum Response Factor Signal Pathway Signal Transduction Site Smooth Muscle Smooth Muscle Myocytes Specimen Techniques Testing Training Training Programs Transforming Growth Factor Beta 2 Transforming Growth Factor beta Transforming Growth Factors Translating Universities Wound Healing abstracting analog base career career development cytokine effective therapy experience human disease in vivo indium-bleomycin instructor novel prevent programs research study response skills therapeutic development

项目摘要

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)

描述（由申请人提供）：该提案概述了一项为期 5 年的肺学术职业发展培训计划。首席研究员 (PI) 已在芝加哥大学完成内科住院医师实习，随后又在芝加哥大学获得肺科和重症监护医学专科医师资格。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）。他将通过独特的细胞信号传导培训计划扩展他的科学技能。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 博士将指导首席研究员的科学发展。他是细胞信号传导领域的知名研究者，也是致力于将 PI 培养成为独立临床医生科学家的杰出导师。 Julian Solway 博士是一位杰出的医师兼研究员，曾成功培训了许多临床医师兼科学家，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，由细胞信号传导、肺生理学和分子生物学领域卓有成就的科学家组成的咨询委员会将为科学和职业发展做出贡献。研究重点是血清反应因子（SRF）在肺纤维化情况下介导肌成纤维细胞分化中的作用。 Pis 初步数据显示，1) SRF 是促纤维化细胞因子 TGF-β 诱导的肌成纤维细胞分化所必需的，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可减弱肌成纤维细胞分化作用。小鼠模型中肺纤维化的发展。因此，总体假设是TGF-β通过激活血清反应因子刺激肌成纤维细胞分化，并且可以通过靶向细胞培养物和体内的SRF活性来抑制TGF-β诱导的肌成纤维细胞分化。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，重点关注肌成纤维细胞分化。这些信号通路的识别可能会导致针对这种进行性致命疾病的新药物治疗的开发。（摘要完）

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Control of myofibroblast differentiation by microtubule dynamics through a regulated localization of mDia2.

通过调节 mDia2 的定位，通过微管动力学控制肌成纤维细胞分化。

DOI：
发表时间：
2013-05-31
期刊：
影响因子：
0
作者：
Sandbo, Nathan;Ngam, Caitlyn;Torr, Elizabeth;Kregel, Steve;Kach, Jacob;Dulin, Nickolai
通讯作者：
Dulin, Nickolai

The Novel mTOR Complex 1/2 Inhibitor P529 Inhibits Human Lung Myofibroblast Differentiation.

新型 mTOR 复合物 1/2 抑制剂 P529 抑制人肺肌成纤维细胞分化。

DOI：
发表时间：
2017
期刊：
影响因子：
4
作者：
Ferguson, Keith T;Torr, Elizabeth E;Bernau, Ksenija;Leet, Jonathan;Sherris, David;Sandbo, Nathan
通讯作者：
Sandbo, Nathan

Regulation of myofibroblast differentiation and bleomycin-induced pulmonary fibrosis by adrenomedullin.

肾上腺髓质素调节肌成纤维细胞分化和博莱霉素诱导的肺纤维化。

DOI：
10.1152/ajplung.00262.2012
发表时间：
2013-06-01
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
Jacob Kach;N. S;bo;bo;N. Sethakorn;Jesse W. Williams;E. Reed;Jennifer La;X. Tian;S. Brain;K. Rajendran;R. Krishnan;A. Sperling;K. Birukov;N. Dulin
通讯作者：
N. Dulin

Myofibroblasts exhibit enhanced fibronectin assembly that is intrinsic to their contractile phenotype.

肌成纤维细胞表现出增强的纤连蛋白组装，这是其收缩表型所固有的。

DOI：
发表时间：
2015-03-13
期刊：
影响因子：
0
作者：
Torr, Elizabeth E;Ngam, Caitlyn R;Bernau, Ksenija;Tomasini;Acton, Benjamin;Sandbo, Nathan
通讯作者：
Sandbo, Nathan

Megakaryoblastic leukemia-1 is required for the development of bleomycin-induced pulmonary fibrosis.

巨核细胞白血病-1 是博莱霉素诱导的肺纤维化发生所必需的。

DOI：
发表时间：
2015-03-27
期刊：
影响因子：
5.8
作者：
Bernau, Ksenija;Ngam, Caitlyn;Torr, Elizabeth E;Acton, Benjamin;Kach, Jacob;Dulin, Nickolai O;Sandbo, Nathan
通讯作者：
Sandbo, Nathan