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 #
5U19AI095219-03
Application #
8502613
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
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$1,952,502
Indirect Cost
$825,249
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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