Role of TGF beta in Airway Hyperresponsiveness in Vivo

描述(由申请人提供)： 申请者是芝加哥大学医学系的高级研究员，多年来一直在那里从事国际知名的肺科基础科学和临床研究。芝加哥大学为Camoretti-Mercado博士作为基础和翻译研究人员的发展提供了丰富的环境。有才华、有经验和敬业的导师和共同导师，一个有经验的顾问和合作者团队，以及一个多学科的培训计划结合在一起，提供关键的指导和建议，并提高候选人在动物生理学和转基因方面的技术和科学技能。这一K01奖项将有助于实现这些目标，并有助于候选人成功过渡为一名独立调查人员。申请者的直接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体生物体为中心的研究。Camoretti-Mercado博士的长期目标是在细胞和分子水平上阐明正常和疾病肌肉功能的基本方面。候选人调查的最终目的是为哮喘等肺部疾病的发病机制和可能的治疗方法提供见解。哮喘是一种常见的慢性肺部疾病，以呼吸道功能和结构异常为特征。哮喘的特征是气道平滑肌(ASM)增多或重构，以及对收缩药或气道高反应性(AHR)的过度敏感，这些都会导致气流阻塞的恶化。令人惊讶的是，肌肉在这些反应中的作用并没有得到明确的定义。虽然炎症介质转化生长因子β(TGF(3))在哮喘肺组织中升高，但其在ASM重塑和AHR中的作用尚不清楚。这项建议的主要目标是确定转化生长因子|3是否、何时以及如何改变两种实验性哮喘小鼠的ASM结构和功能。我们提出了两个主要目标：1)通过检测TGFp是否通过靶向过表达Smad？或显性阴性的TGFp受体II可阻止ASM重塑和ARM。2)确定TGFp的直接作用在慢性变应原攻击小鼠ASM中的作用，表现出ASM蓄积和呼吸道力学的异常，与TGFp过度分泌所致的异常相似。这些研究的结果将为TGFP如何诱导ASM结构和功能异常以及这种异常在实验性哮喘中是否具有生理学意义提供重要的新见解。它们也将是建立高质量的翻译研究项目和获得独立的联邦资金的基础。(摘要结束)

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)