This Proposal for support of an Asthma and Allergic Disease Cooperative Research Center (AADCRC) grant is focused on the mechanistic basis of aspirin-exacerbated respiratory disease (AERD), a distinctive clinical syndrome that accounts for a disproportionate percentage of individuals with severe asthma and recurrent nasal polyps. AERD is associated with both characteristic clinical reactions to ingestion of nonselective inhibitors of cyclooxygenase (COX), persistently elevated generation of the cysteinyl leukotrienes (cys-LTs), especially during reactions to aspirin, and selective airway hyperresponsivness to leukotriene E4 (LTE4), the most stable and abundant of the cys-LTs. We have discovered a molecular pathway through which LTE4 induces pulmonary inflammation (requiring P2Y12 receptors and platelets) and vascular leak (requiring a putative novel LTE4 receptor, GPR99). We have also discovered that leukocytes from individuals with AERD display a defect in expression of COX-2 and COX-2-dependent generation of prostaglandin E2 (essential to maintain homeostasis in AERD), and that this reverses with desensitization to aspirin. We have also found that platelets and leukocytes from individuals with AERD lack the EP2 receptor for PGE2. A team of highly accomplished investigators with complementary skills will apply cellular, molecular, and whole animal strategies, combined with a proof-of-concept clinical trial to determine the cellular and molecular basis for these findings, their relevance to disease pathophysiology, and their amenability to therapy. Project 1 (J. Boyce, PI) focuses on the physiologic and functional consequences of EP2 receptor deficiency, and determines its epigenetic basis. Project 2 (Y. Kanaoka, PI) will verify the identity and function of GPR99 and determine its susceptibility to desensitization and its requirement for downstream effectors (platelets, P2Y12, and thromboxane) to elicit physiologic responses. Project 3 (E. Israel, PI) will determine the efficacy of P2Y12 antagonism on the severity of clinical reactions to aspirin, and the mechanism by which aspirin treatment restores COX-2-dependent PGE2 generation. The coordination of the AADCRC is enhanced by an administrative Core.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-PA-I (M1))
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Minnicozzi, Michael
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Brigham and Women's Hospital
United States
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Cahill, Katherine N; Bensko, Jillian C; Boyce, Joshua A et al. (2015) Prostaglandin D?: a dominant mediator of aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 135:245-52
Laidlaw, Tanya M; Cutler, Anya J; Kidder, Molly S et al. (2014) Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 133:1692-701.e3
Parsons, Matthew W; Li, Li; Wallace, Aaron M et al. (2014) Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization. J Immunol 192:1361-71
Cardet, Juan Carlos; White, Andrew A; Barrett, Nora A et al. (2014) Alcohol-induced respiratory symptoms are common in patients with aspirin exacerbated respiratory disease. J Allergy Clin Immunol Pract 2:208-13.
Liu, Tao; Laidlaw, Tanya M; Katz, Howard R et al. (2013) Prostaglandin E2 deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes. Proc Natl Acad Sci U S A 110:16987-92
Laidlaw, Tanya M; Boyce, Joshua A (2013) Pathogenesis of aspirin-exacerbated respiratory disease and reactions. Immunol Allergy Clin North Am 33:195-210
Kanaoka, Yoshihide; Maekawa, Akiko; Austen, K Frank (2013) Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand. J Biol Chem 288:10967-72
Cummings, Hannah E; Liu, Tao; Feng, Chunli et al. (2013) Cutting edge: Leukotriene C4 activates mouse platelets in plasma exclusively through the type 2 cysteinyl leukotriene receptor. J Immunol 191:5807-10
Laidlaw, Tanya M; Kidder, Molly S; Bhattacharyya, Neil et al. (2012) Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood 119:3790-8
Oyoshi, Michiko K; He, Rui; Kanaoka, Yoshihide et al. (2012) Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis. Proc Natl Acad Sci U S A 109:4992-7