Role of TGF beta in Airway Hyperresponsiveness in Vivo

TGFβ 在体内气道高反应性中的作用

基本信息

批准号：
7897768
负责人：
BLANCA CAMORETTI-MERCADO
金额：
$ 12.98万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-07 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897768
关键词：
Abbreviations Actins Allergens Animal Model Animals Antibodies Asthma Award Basic Science Breathing Cells Cellular biology Chicago Chronic Chronic lung disease Clinical Research Control Animal Development Dominant-Negative Mutation Electroporation Environment Foundations Funding Gene Transfer Techniques Goals In Vitro Inflammation Mediators Intervention Investigation Life Lung Lung diseases Mechanics Medicine Mentored Research Scientist Development Award Mentors Methodology Modeling Molecular Mus Muscle Muscle function Myosin Heavy Chains Obstruction Pathogenesis Physiology Plasmids Postdoctoral Fellow Preparation Property Research Research Personnel Respiratory physiology Role Secure Signal Transduction Smooth Muscle Testing Training Transforming Growth Factor beta Transgenes Transgenic Mice Transgenic Organisms Translational Research Universities Whole Organism abstracting airway hyperresponsiveness airway remodeling bronchial epithelium experience in vivo inhibitor/antagonist insight methacholine mouse model multidisciplinary muscle form muscular structure novel strategies overexpression prevent programs receptor respiratory smooth muscle response skills

项目摘要

DESCRIPTION (provided by applicant): The applicant is a Senior Research Associate in the Department of Medicine at The University of Chicago, where internationally renowned basic science and clinical research in pulmonary has been ongoing for many years. The University of Chicago provides a rich environment for Dr. Camoretti-Mercado's development as a basic and translational researcher. Talented, experienced and dedicated mentor and co-mentor, a team of accomplished advisers and collaborators, and a multidisciplinary training plan are put together to provide critical guidance and advice, and enhance the candidate's technical and scientific skills in animal physiology and transgenesis. This K01 award will be instrumental towards these goals and for the candidate's successful transition to become an independent investigator. The applicant's immediate goal is to shift the research focus in molecular and cell biology from in vitro experimentation to studies centered in whole organisms. The long-term goal of Dr. Camoretti-Mercado is to elucidate fundamental aspects of normal and diseased muscle function at both cellular and molecular level. The ultimate purpose of the candidate's investigations is to provide insights into the pathogenesis and potential treatment for disorders of the lung such as asthma. Asthma is a common chronic lung disease characterized by functional and structural abnormalities in the airway. Increased airway smooth muscle (ASM) abundance or remodeling, and exaggerated sensitivity to contractile agents or airway hyperresponsiveness (AHR), which contribute to worsen airflow obstruction, are hallmarks of asthma. Surprisingly, the role of the muscle in these responses is not definitively defined. Although the inflammatory mediator transforming growth factor beta (TGF(3) is elevated in asthmatic lungs, its role in ASM remodeling and AHR is poorly understood. The major objective of this proposal is to determine whether, when, and how TGF|3 alters ASM structure and function in two experimental mouse models of asthma. We propose 2 major aims: 1) Elucidate whether TGFp induces ASM structural and functional abnormalities through direct action on ASM, by testing whether selective disruption of TGFp signaling in SM, through targeted overexpression of Smad? or dominant negative TGFp receptor II prevents ASM remodeling and ARM. 2) Determine the contribution of direct TGFp action on ASM in mice subjected to chronic allergen challenge, which demonstrate abnormalities of ASM accumulation and airway mechanics that parallel those caused by TGFp oversecretion. Results from these studies will provide important new insights into how TGFp induces aberrant ASM structure and function, and whether such abnormalities are physiologically important in experimental asthma. They will also be the foundation for building a high-quality translational research program and securing independent federal funding. (End of Abstract)

描述（由申请人提供）：申请人是芝加哥大学医学系的高级研究助理，国际知名的肺部基础科学和临床研究已经进行了很多年。芝加哥大学为Camoretti-Mercado博士作为基本和翻译研究人员的发展提供了丰富的环境。有才华，经验丰富，敬业的导师和联合学者，成熟的顾问和合作者团队，以及一个多学科培训计划，以提供关键的指导和建议，并增强候选人在动物生理和转基因方面的技术和科学技能。该K01奖将对这些目标以及候选人的成功过渡成为独立调查员的作用。申请人的近期目标是将分子和细胞生物学的研究重点从体外实验转移到以整个生物为中心的研究。 Camoretti-Mercado博士的长期目标是阐明在细胞和分子水平上均在肌肉功能的基本方面。候选人研究的最终目的是提供有关肺部疾病（例如哮喘）的发病机理和潜在治疗的见解。哮喘是一种常见的慢性肺部疾病，其特征是气道功能和结构异常。气道平滑肌（ASM）丰度或重塑增加，对收缩剂或气道高反应性（AHR）的敏感性夸大，这会导致气流阻塞恶化，这是哮喘的标志。令人惊讶的是，肌肉在这些反应中的作用并未明确定义。尽管哮喘肺中转化生长因子β（TGF（3）的转化较高（TGF（3）升高，其在ASM重塑和AHR中的作用很差。该提议的主要目的是确定TGF | 3 | 3在两个实验性小鼠模型中是否会在ASM结构和功能中如何改变ASTHMA的质量和功能。通过对ASM的直接作用，通过测试SM中TGFP信号的选择性破坏，通过靶向SMAD的靶向过表达来测试TGFP信号传导的异常吗？或显性负TGFP受体II可防止ASM重塑和手臂。 2）确定受到慢性变应原挑战的小鼠对ASM的直接TGFP作用的贡献，这表明ASM积累和气道机械的异常是由TGFP过度分泌引起的。这些研究的结果将为TGFP如何诱导异常的ASM结构和功能以及这种异常在实验性哮喘中是否重要。他们还将成为建立高质量的转化研究计划并获得独立联邦资金的基础。（抽象的结尾）