Role of TGF beta in Airway Hyperresponsiveness in Vivo

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，该大学多年来一直在进行国际知名的肺部基础科学和临床研究。芝加哥大学为Camoretti-Mercado博士作为基础和转化研究人员的发展提供了丰富的环境。有才华，经验丰富，敬业的导师和共同导师，一个有成就的顾问和合作者团队，以及多学科的培训计划放在一起，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。这个K 01奖将有助于实现这些目标，并为候选人的成功过渡，成为一个独立的调查员。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患病肌肉功能的基本方面。候选人研究的最终目的是深入了解哮喘等肺部疾病的发病机制和潜在治疗方法。哮喘是一种常见的慢性肺部疾病，其特征在于气道的功能和结构异常。增加的气道平滑肌（ASM）丰度或重塑，以及对收缩剂或气道高反应性（AHR）的过度敏感性，这有助于恶化气流阻塞，是哮喘的标志。令人惊讶的是，肌肉在这些反应中的作用并没有明确定义。虽然炎症介质转化生长因子β（TGF β）在哮喘肺中升高，但其在ASM重塑和AHR中的作用尚不清楚。本提案的主要目标是确定是否、何时以及如何进行TGF| 3改变了两种实验性哮喘小鼠模型的ASM结构和功能。我们提出两个主要目标：1）阐明TGF β是否通过直接作用于ASM诱导ASM结构和功能异常，通过测试是否通过靶向过表达Smad选择性破坏SM中的TGF β信号传导？2）在经受慢性过敏原攻击的小鼠中确定TGF β对ASM的直接作用的贡献，这表明ASM积累和气道力学的异常与TGF β过分泌引起的那些异常平行。这些研究的结果将为TGF β如何诱导异常的ASM结构和功能，以及这些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。他们也将是建立一个高质量的转化研究计划和确保独立的联邦资金的基础。(End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)