The Cysteinyl Leukotriene E4 Receptor, GPR99, Orchestrates Airway Epithelial Cell Differentiation and Type 2 Pulmonary Inflammation

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PROJECT SUMMARY/ABSTRACT: This proposal details a five-year plan to provide the candidate, Lora Bankova, MD, with the knowledge and expertise to become an independent investigator in the field of Allergy and Immunology. The studies focus on a previously unrecognized role of the stable cysteinyl leukotriene (cysLT) metabolite LTE4 in the control of proximal events leading to development of type 2 immunity to the outdoor mold aeroallergen, Alternaria. Using a combination of cellular and molecular approaches, the candidate will test the hypothesis that GPR99 drives innate type 2 immunity and airway remodeling through the control of epithelial cell activation for IL-25 generation. As LTE4 is the only stable cysLT metabolite and is detected in asthma elicited by allergen, viruses, aspirin, there are significant translational implications for asthma. The short-term goals of this K08 award application are to provide training in advanced imaging techniques, advanced genomic techniques, including RNA-Seq, and human translational research. Dr. Bankova's long-term goal is to develop an independent translational research program studying the innate immune control of allergic disease. During the period of support the candidate will complement her laboratory skills with didactic coursework to develop skills in emerging gene sequencing and editing methods, courses in bioinformatics and systems biology, grant writing, leadership, and the responsible conduct of research germane to the application. This will then facilitate her transition to independence during the third and fourth years of the award. Dr. Bankova will work under the mentorship of Nora Barrett, MD and Joshua Boyce, MD, experts in cysLT biology and mechanisms of inflammation. Dr. Bankova has also assembled a team of extraordinary scientists, including Drs. Yoshihide Kanaoka, Carla Kim, Bruce Levy, Howard Katz, and K. Frank Austen, who have committed their time, resources, and expertise to facilitate her career development and research goals. Under their mentorship and guidance, in an ideal scientific environment at the Brigham and Women's Hospital, training in immunology, didactic curriculum, and career development plan will position the candidate to secure independent NIH funding and to establish herself as a physician scientist with a focus on the role of mast cells and cysLTs in instructing epithelial cell activation to guide immune bias at mucosal surfaces.