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.
/Public Health Relevance Statement Asthma is a common disease that affects up to 15% of the population of the United States, and about one in every ten adults with asthma develops life-threatening attacks of asthma when they ingest aspirin or other similar medications. These individuals suffer from chronic sinus disease and severe asthma and have very few options for treatment. In this proposal we seek to understand the mechanisms responsible for aspirin-exacerbated respiratory disease in order to provide new insights into the cause, diagnosis, and treatment of the disorder.
|Cahill, Katherine N; Johns, Christina B; Cui, Jing et al. (2017) Automated identification of an aspirin-exacerbated respiratory disease cohort. J Allergy Clin Immunol 139:819-825.e6|
|Samuchiwal, Sachin K; Balestrieri, Barbara; Raff, Hannah et al. (2017) Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway. J Biol Chem 292:8195-8206|
|Yamaguchi, Munehiro; Zacharia, Jennifer; Laidlaw, Tanya M et al. (2016) PLA2G5 regulates transglutaminase activity of human IL-4-activated M2 macrophages through PGE2 generation. J Leukoc Biol 100:131-41|
|Shah, Neelam H; Schneider, Thomas R; DeFaria Yeh, Doreen et al. (2016) Eosinophilia-Associated Coronary Artery Vasospasm in Patients with Aspirin-Exacerbated Respiratory Disease. J Allergy Clin Immunol Pract 4:1215-1219|
|Cahill, Katherine N; Raby, Benjamin A; Zhou, Xiaobo et al. (2016) Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease. Am J Respir Cell Mol Biol 54:34-40|
|Buchheit, Kathleen M; Cahill, Katherine N; Katz, Howard R et al. (2016) Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 137:1566-1576.e5|
|Liu, Tao; Kanaoka, Yoshihide; Barrett, Nora A et al. (2015) Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway. J Immunol 195:3537-45|
|Lee-Sarwar, Kathleen; Johns, Christina; Laidlaw, Tanya M et al. (2015) Tolerance of daily low-dose aspirin does not preclude aspirin-exacerbated respiratory disease. J Allergy Clin Immunol Pract 3:449-51|
|Laidlaw, Tanya M; Boyce, Joshua A (2015) Platelets in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 135:1407-14; quiz 1415|
|Liu, Tao; Garofalo, Denise; Feng, Chunli et al. (2015) Platelet-driven leukotriene C4-mediated airway inflammation in mice is aspirin-sensitive and depends on T prostanoid receptors. J Immunol 194:5061-8|
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