Targeting Epithelial WNK1 to Enhance Airway Host Defense

Project Summary/ Abstract This proposal describes a five-year career development plan intended to facilitate Tayyab Rehman, MD’s growth into an outstanding physician-scientist and a leader in the fields of airway biology and airway host defense. Research Plan: Bronchiectasis is a leading cause of morbidity and healthcare utilization worldwide. Despite available treatments, people with bronchiectasis experience high rates of infections (especially with Pseudomonas aeruginosa and Staphylococcus aureus), persistent airway colonization, recurrent infections, exacerbations, accelerated loss of lung function, antibiotic resistance, heavy treatment burden, and reduced health-related quality of life. These factors indicate limitations of current treatment regimens and point to a strong need for novel strategies that enhance endogenous host defense mechanisms. Airway epithelium and the overlying airway surface liquid (ASL) together form the first line of defense against pathogens entering the airways. The epithelium also plays an important role in recruiting innate immune cells to fight off pathogens. Dr. Rehman’s preliminary studies suggest critical involvement of WNK1 (with-no-lysine [K] kinase isoform 1) in these key innate host defense processes, but the underlying mechanisms remain unclear. This proposal will test the hypothesis that reducing epithelial WNK1 enhances key airway host defenses by modulating distinct membrane transport processes. Aim 1 will determine the mechanism by which reducing epithelial WNK1 increases ASL- mediated bacterial killing. Aim 2 will identify the mechanism by which reducing WNK1 lowers ASL viscosity and relieves mucus obstruction. Aim 3 will elucidate the mechanism by which reducing WNK1 increases recruitment of highly activated innate immune cells in response to airway bacterial challenge. These aims will be achieved using a combination of in vitro (primary differentiated human airway epithelia) and in vivo (airway secretory cell or ciliated cell specific Wnk1 knockout) models. Applicant and Training Plan: Tayyab Rehman, MD has completed training in Internal Medicine, and Pulmonary and Critical Care Medicine. He has acquired extensive research experience in the last five years studying airway surface liquid, CFTR regulation, ion transport, inflammation, and acid-base balance in human airway epithelia. The proposed training will provide new knowledge in epithelial WNK signaling and its role in regulating key airway host defenses. Technical training includes advanced microscopy, live-cell imaging, kinase signaling assays, cell- specific inducible knockout mouse modeling, primary cell co-culture, lung immunophenotyping, and phagocytosis assays. The training plan, mentorship team, and mentored research will greatly enrich Dr. Rehman’s career by providing him with additional knowledge and skills necessary to become an independent and highly successful physician-scientist, dedicated to enhancing treatment options and thus improving outcomes for a wide variety of lung disorders.