PATHOGENESIS OF CF AND PCD LUNG DISEASE

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The goal of this clinical research project is to increase the understanding of the molecular, cellular, and organ-level pathogenesis of non-asthmatic airways disease, which will lead to better diagnosis and treatment of lung disease. The mucociliary apparatus is a major component of normal airway host defense, which depends on the integration of airway epithelial regulation of ion composition and volume of airway surface liquid, and ciliary structure and fiinction. Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are two genetic models of lung disease, which lead to abnormal airway clearance and chronic lung disease. The research project is sub-divided into two major components. Specific Aim I will define the relationship between mutant CFTR and expression of lung disease at a molecular, cellular and clinical level. In specific aim II, work will focus on defining the genetic mutations associated with PCD, including rigorous quantitation and definition of different cell biologic and ciliary ultrastructural phenotypes in PCD, to allow testing initially via the candidate gene approach. These research goals will be undertaken in the overall context of career development for clinical research in human subjects, with emphasis in the initial years of funding on course work and completion of the projects related to CF. Later years of funding will concentrate on the research in PCD. Thus, the research will combine practical experience in human research with coursework in genetics, molecular biology techniques, biostatistics, clinical study design, and the responsible conduct of human research. The work will be supervised by a senior clinical investigator mentor. Training will also be provided by collaboration with experts in a variety of fields, including molecular biology, clinical genetics, electrophysiology, and cell biology. The environment at UNC-Chapel Hill is rich in resources for this clinical research career development, offering formal courses, and experts in a variety of patient-oriented research fields. This award will greatly enhance the future ability of the applicant to conduct independent, high-quality clinical research.