This proposal describes a 5-year, comprehensive training program designed to provide Dr. Kreindler with the education and mentorship necessary to launch a successful career in academic medicine. Dr. Kreindler completed his postdoctoral fellowship in Pediatric Pulmonology, and is a full-time Assistant Professor of Pediatrics in the Division of Pediatric Pulmonology. His long-term goal is to become an independently-funded clinician scientist with an expertise in the cell biology and physiology of the lung. Accordingly, he will complete formal didactic work in cell biology and physiology, biostatistics, and research design;will have a broad-based experience in the laboratory with exposure to electrophysiology, protein biochemistry, molecular biology, and fluorescence microscopy. Dr. Raymond Frizzell, an internationally recognized expert in cell biology and physiology will serve as Dr. Kreindler's primary sponsor and mentor. Exposure to cigarette smoke causes clinically significant lung disease. Notably, the negative effects of cigarette smoking are not confined to smokers, but extend to those exposed to environmental tobacco smoke. These are often children who are unwillingly exposed and have little opportunity for avoidance. Cigarette smoke is known to damage cilia, increase mucus production, and alter inflammation, such that a cigarette smoke exposed epithelium would need to increase fluid secretion to maintain homeostasis with respect to mucociliary clearance. However, data from our lab and others has shown that cigarette smoke inhibits chloride secretion by airway epithelia, further contributing to the problem of impaired mucociliary clearance. The mechanisms by which this inhibition take place remain incompletely characterized. The hypothesis of this proposal states that cigarette smoke inhibits chloride secretion via oxidation-dependent inhibition of the cAMP-dependent apical anion conductance and inhibits the sodium, potassium, chloride cotransporter. The proposed studies utilize basic and advanced electrophysiology techniques, fluorescence microscopy, and protein biochemical techniques to study the effect of cigarette smoke on ion transport of human bronchial epithelial cells. Changes in chloride secretion will be correlated with changes in airway surface liquid height and mucociliary clearance with the hypothesis that decreases in chloride secretion will correlate with decreased periciliary fluid height and decreased mucociliary clearance.
