This proposal seeks to determine the mechanisms and receptors by which leukotriene (LT)E4, the most stable ligand of the cysteinyl leukotrienes (cys-LTs), activates mast cells (MCs) and promotes pulmonary inflammation. An abundance of historical information supports the existence of a distinct receptor for LTE4 Our published studies demonstrate that LTE4 is the most potent cys-LT for both for human MC proliferation in vitro and potentiation of airway inflammation in vivo, and it activates human MCs by a mechanism independent of CysLT1R and CysLT2R. Our Preliminary Studies strongly indicate that the P2Y12 receptor, an adenosine diphosphate-responsive GPCR, is also the LTE4-reactive receptor (hereafter termed P2Y12/CysLT3R) mediating the effects of LTE4 on MCs in vitro and on lung pathology in vivo. The central hypothesis is that LTE4, the weakest agonist of the cys-LTs at their known receptors, is the most relevant cys-LT for promoting allergic mucosal inflammation. A corollary hypothesis is that the actions of LTE4 are mediated by a previously unrecognized cys-LT-reactive G protein-coupled receptor (GPCR), hereafter referred to as """"""""P2Y12/CysLT3R"""""""".
Aim 1 uses in vitro approaches to prove that P2Y12/CysLT3R is a true LTE4-reactive receptor.
Aim 2 seeks to prove that P2Y12/CysLT3R accounts for the striking proinflammatory effects of LTE4 in the lung in vivo, and to identify the essential cellular targets of this effect. The findings are expected to have immediate implications for asthma pathophysiology and treatment.

Public Health Relevance

Mast cells are crucial to allergic reactions and important in asthma. Cysteinyl leukotrienes are important chemical mediators of asthma and allergy. This Project will define the ways that cysteinyl leukotrienes, especially leukotriene E4, work to promote mast cell development and inflammation in the lung. The project will also reveal whether a particular molecule called P2Y12 might be a useful new drug target for asthma treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078908-02
Application #
7895671
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dong, Gang
Project Start
2009-07-17
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$397,733
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Liu, Tao; Barrett, Nora A; Kanaoka, Yoshihide et al. (2018) Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity. J Immunol 200:915-927
Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Pan, Dingxin; Buchheit, Kathleen M; Samuchiwal, Sachin K et al. (2018) COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity. J Allergy Clin Immunol :
Cahill, Katherine N; Katz, Howard R; Cui, Jing et al. (2017) KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376:1911-1920
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
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
Kondeti, Vinay; Al-Azzam, Nosayba; Duah, Ernest et al. (2016) Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3. J Allergy Clin Immunol 137:289-298
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
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
Boyce, Joshua A; Barrett, Nora A (2015) Cysteinyl leukotrienes: an innate system for epithelial control of airway smooth muscle proliferation? Am J Respir Crit Care Med 191:496-7

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