The inflammatory role of the platelet in aspirin-exacerbated respiratory disease.

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DESCRIPTION (provided by applicant): This proposal details a five-year plan to provide the candidate, Tanya Laidlaw, 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 for platelets as effectors of aspirin-exacerbated respiratory disease (AERD). AERD is characterized by asthma, recurrent nasal polyps, and respiratory reactions that occur upon ingestion of aspirin or other inhibitors of cyclooxygenase-1. Although the cause is unknown, the syndrome is consistently associated with tissue eosinophilia and elevated generation of cysteinyl leukotrienes, the latter of which may reflect a disturbance in the production of prostaglandin E2 or the function of its receptors (EP receptors). The candidate has discovered that platelets from individuals with AERD demonstrate decreased function of two prostaglandin E2 receptors, EP2 and EP4, which lowers the threshold for activation of their platelets and allows for increased platelet adhesion onto inflammatory granulocytes and monocytes. As a result, the blood of individuals with AERD contains substantially more platelet-leukocyte aggregates than does the blood of aspirin tolerant controls. Using a combination of cellular, biochemical, and molecular approaches, the candidate will test the hypothesis that abnormal EP2 and EP4 signaling on platelets unifies the phenomena of leukotriene overproduction, tissue eosinophilia, and aspirin-induced reactions in patients with AERD. The results from these studies will advance our understanding of the pathogenesis of AERD. During the period of support the candidate will complement her laboratory skills with didactic coursework to develop skills in clinical study design, advanced biostatistics, and scientific writing. This will then facilitate her transition to independence during the third and fourth yearsof the award. Dr. Laidlaw will work under the mentorship of Joshua 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. Dr. Laidlaw has also assembled a team of extraordinary physician scientists, including Drs. Elliot Israel, Mariana Castells, 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 and clinical environment at the BWH, the translational work, 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 AERD, a relatively neglected area of investigation.