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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI095219-02
Application #
8302288
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Program Officer
Minnicozzi, Michael
Project Start
2011-07-15
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$1,787,094
Indirect Cost
$880,346
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Bankova, Lora G; Lai, Juying; Yoshimoto, Eri et al. (2016) Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99. Proc Natl Acad Sci U S A 113:6242-7
Lee, Min Jung; Yoshimoto, Eri; Saijo, Shinobu et al. (2016) Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity. J Immunol 197:278-87
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
Dwyer, Daniel F; Barrett, Nora A; Austen, K Frank et al. (2016) Expression profiling of constitutive mast cells reveals a unique identity within the immune system. Nat Immunol 17:878-87
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
Cardet, Juan Carlos; Israel, Elliot (2015) Update on reslizumab for eosinophilic asthma. Expert Opin Biol Ther 15:1531-9
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
Cahill, Katherine N; Bensko, Jillian C; Boyce, Joshua A et al. (2015) Prostaglandin Dâ‚‚: a dominant mediator of aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 135:245-52
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

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