Structural and Biochemical Basis of the Vitamin K cycle

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DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the lung thought to be mediated exclusively by the products of Th2 cells. Preliminary evidence suggests that genetic susceptibility to allergen-induced airway hyperresponsiveness (AHR) results from differential epithelial cell responsiveness to inhaled allergen. In susceptible animals, epithelial cell-derived factors selectively enhance the activation, and production of Th17-skewing cytokines by pulmonary myeloid dendritic cells (mDC). However, it is unclear how the epithelium enhances mDC capacity to promote Th17 responses, or how Th17 and Th2 cells collaborate to exacerbate asthma. The aims are: 1) to identify the epithelial cell factors responsible for promoting the activation of pulmonary mDCs, 2) identify the role of Th17 responses in exacerbating the Th2-associated pathology, and 3) identify novel asthma susceptibility genes using a novel tool, recombinant inbred mouse strains from the Collaborative Cross. The studies and career development activities outlined in this proposal will allow the candidate to achieve his long term career goal of becoming an independent investigator with a focus on dissecting how genetic differences influence the ability of epithelial cells to regulate dendritic cell activity, and promote Th17 T cell responses. To acquire the necessary skill set, the candidate's K99 research will take place in the lab of Marsha Wills-Karp, an expert in the field of asthma genetics, and pulmonary epithelial culture techniques, where he will acquire expertise in the culture and manipulation of murine pulmonary epithelium. Moreover, during the mentored phase, the candidate will acquire expertise in the use of genetic and bioinformatics approaches to identify novel asthma susceptibility genes, through advanced training at the University of Cincinnati, and Jackson Laboratories. This training will be essential for completing the research proposed for the independent phase of this award. Subsequent studies to dissect the function of identified asthma susceptibility genes in murine and human populations will form the basis of future R01 applications, assisting in the transition to scientific independence.