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.
|Comer, Brian S; Camoretti-Mercado, Blanca; Kogut, Paul C et al. (2014) MicroRNA-146a and microRNA-146b expression and anti-inflammatory function in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 307:L727-34|
|Schuliga, Michael; Javeed, Aqeel; Harris, Trudi et al. (2013) Transforming growth factor-?-induced differentiation of airway smooth muscle cells is inhibited by fibroblast growth factor-2. Am J Respir Cell Mol Biol 48:346-53|
|Xia, Yuxiu C; Redhu, Naresh Singh; Moir, Lyn M et al. (2013) Pro-inflammatory and immunomodulatory functions of airway smooth muscle: emerging concepts. Pulm Pharmacol Ther 26:64-74|
|Gerthoffer, William T; Solway, Julian; Camoretti-Mercado, Blanca (2013) Emerging targets for novel therapy of asthma. Curr Opin Pharmacol 13:324-30|
|Hofmann Bowman, M A; Heydemann, A; Gawdzik, J et al. (2011) Transgenic expression of human S100A12 induces structural airway abnormalities and limited lung inflammation in a mouse model of allergic inflammation. Clin Exp Allergy 41:878-89|
|Ma, Lan; Brown, Melanie; Kogut, Paul et al. (2011) Akt activation induces hypertrophy without contractile phenotypic maturation in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 300:L701-9|
|Camoretti-Mercado, Blanca (2009) Targeting the airway smooth muscle for asthma treatment. Transl Res 154:165-74|