Project Summary Multiple studies by our investigative team and others demonstrate that prostaglandin E2 (PGE2) regulates the function of multiple cell types in the lung, including resident structural cells, nerves, and infiltrating blood cells. Although PGE2 has been shown to mediate numerous anti-inflammatory effects, it has also been shown to promote certain pro-inflammatory actions, as well as undesirable side effects, the most prominent being cough, that have stalled efforts to exploit its clinical potential. The numerous and complex effects of PGE2 are due, in large part, to the existence of 4 different EP receptor subtypes. Each of EP receptor subtypes (EP1, 2, 3, and 4) promotes different signaling and function when stimulated by PGE2, while being differentially expressed in the numerous cell types in the lung. The goal of this project is to take advantage of recent advances in EP receptor pharmacology and research capabilities, to identify the optimal EP receptor targeting strategy to treat asthma. Our central hypothesis is that EP receptors mediate a complex array of functions in the lung and in allergic lung inflammation, and selective targeting of EP subtypes can provide optimal therapy for asthma by ameliorating lung inflammation, airway hyperresponsiveness (AHR), and airway remodeling, while avoiding promotion of cough. We have assembled a multi-PI, international team capable of exhaustively characterizing EP subtype function, and the utility of EP targeting for the purpose of asthma therapy. Three Aims will be pursued that constitute a robust analysis of the cooperative (positive and negative) roles of EP receptors in cell, tissue, and in vivo models. Aim 1 will employ rodent models of allergic lung inflammation and assess the effect of multiple combinations of EP agonists and antagonists on lung inflammation, airway remodeling, and airway hyperresponsiveness. Aim 2 will focus on EP receptor signaling and regulation of relevant human and rodent cell (airway smooth muscle, airway epithelia, and mast cells) functions. Aim 3 will employ cell, tissue, and in vivo models to detail EP receptor regulation of cough. Upon conclusion of these studies we will have identified a novel therapeutic approach that has long been suspected but has eluded the research community for decades.