TGF-Beta Regulates CFTR-Mediated Airway Smooth Muscle Dysfunction

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

PROJECT SUMMARY/ABSTRACT Cystic fibrosis (CF) is a lethal genetic disorder characterized by progressive lung disease and airway obstruction. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR). Patients with CF often develop airway hyperresponsiveness (AHR) related to smooth muscle dysfunction, which worsens airway obstruction and portends faster lung function decline. TGF is a genetic modifier of CF, with higher TGF levels linked to more severe lung disease. TGF also causes worse AHR and smooth muscle abnormalities in CF mice versus non-CF mice. It is unknown how TGF modifies CF lung disease or drives CF smooth muscle dysfunction. This proposal seeks to investigate TGF’s role in CF airway smooth muscle dysfunction. Currently, no therapies directly target smooth muscle abnormalities or TGF signaling in CF. This proposal investigates the overall hypothesis that TGF regulates CFTR-mediated airway smooth muscle dysfunction through effects on both CF epithelial and smooth muscle cells. CF animal and mouse/human primary cell culture models will be used to test the tissue specific function of CFTR in TGF induced lung disease. Aim 1 will determine the role of CFTR dysfunction in airway epithelial cells in mediating TGF-driven lung disease, using TGF exposed epithelial- specific Cftr knockout mice and primary murine and human cell culture models. These studies will focus on epithelial and inflammatory mediators. Aim 2 will test the mechanisms of TGF-induced CF airway smooth muscle dysfunction by examining pulmonary and smooth muscle abnormalities in both smooth muscle-specific Cftr knockout mice and isolated murine and human CF cell culture models. Tests of TGF-mediated AHR, lung function, and smooth muscle contractility will be used to compare CF and non-CF airway smooth muscle function. The PI for this proposal, Dr. Elizabeth Kramer, is a physician scientist in Pulmonary Medicine with a focus on drivers of early CF lung disease. She has a Ph.D. in Molecular and Developmental Biology and an extensive background in mouse models and lung physiology. Her mentors provide complimentary expertise in CF mouse and cell culture models (Dr. A.P. Naren, primary mentor), translational CF research and personalized medicine (Dr. J.P. Clancy, Co-mentor), and translational research design (Dr. Raouf Amin, Co-mentor). These mentors have an established record of success in mentoring academic scientists. They are personally committed to Dr. Kramer’s success in completing this proposal and transitioning to an independent research career. The training plan outlined in this application will provide the applicant with crucial training in innovative laboratory techniques, cutting-edge bioinformatics analysis, immunology, and advanced career skills to successfully establish an independent translational science program. This training plan capitalizes on the excellent environment and support at Cincinnati Children’s Hospital. Addressing these training goals and completing the studies described in this application will build upon Dr. Kramer’s prior expertise in molecular and developmental biology, providing a solid scientific and training platform to launch her independent research career.