The Role of Prostaglandin D2 in the Respiratory Symptoms of Aspirin Exacerbated Respiratory Disease

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 DESCRIPTION (provided by applicant): This proposal details a five-year plan to prepare the candidate, Katherine N. Cahill, MD, for a career as an independent translational investigator positioned to impact our understanding of asthma and allergic disease. The proposed investigations focus on the role of prostaglandin (PG)D2 as a mediator of eosinophilic inflammation in aspirin exacerbated respiratory disease (AERD) . AERD is characterized by asthma, nasal polyposis with chronic eosinophilic sinusitis, excessive cysteinyl leukotriene (cysLT) production, and respiratory reactions to cyclooxygenase-1 inhibitors resulting in a surge in cysLT generation. Aspirin desensitization and high-dose aspirin therapy provide benefit for many patients with AERD without altering cysLT production. The mechanism of action of high-dose aspirin is entirely unknown. The candidate has observed that aspirin-induced respiratory reactions correlate with a rise in the PGD2 to PGE2 (PGD2/PGE2) ratio over basal levels and a fall in peripheral blood eosinophils. Additionally, she has discovered that 8-weeks of high-dose aspirin therapy suppress PGD2 levels while blood eosinophils rise. High-dose aspirin therapy leads to a suppressed PGD2/PGE2 ratio, but only in subjects who report clinical benefit. Employing cellular and biochemical approaches, the candidate will test the hypotheses that PGD2 release during the aspirin-induced reaction results in effector cell migration from the periphery to the respiratory tract and that aspirin leads to clinical benefit by suppressing the PGD2/PGE2 ratio in a dose- dependent manner in subjects with AERD. These studies will advance our understanding of the pathogenesis of AERD and the therapeutic mechanism of aspirin therapy lending support for the trial of PGD2-directed therapeutics in this disease. During the period of support the candidate will leverage her clinical experience in the diagnosis and treatment of AERD, the regional and national referral patient base at her institution's AERD Center, and her laboratory skills while she further develops skills in clinical study design, advanced biostatistics, team leadership, and scientific writing. These skills will enable her to transition to independence during the fourth and fifth years of the award. Dr. Cahill will work under the mentorship of Joshua A. Boyce, MD, an expert in eicosanoid biology and mechanisms of inflammation, who has an excellent record of mentoring young investigators for successful careers in academic medicine. Additionally, Dr. Cahill has assembled a team of extraordinary physician scientists, including Drs. Tanya M. Laidlaw, Elliot Israel, Peter F. Weller and Bruce D. Levy, who have committed their time, resources, and expertise to facilitate her career development and research goals. Their mentorship and the scientific and clinical environment at BWH, along with the translational work 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 mechanistic clinical trials in AERD and asthma.