PKA-dependent regulation of airway epithelial function

Thomas Jefferson University, Philadelphia PA

Investigators

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Abstract

Project Summary/ Abstract G protein-coupled receptors (GPCRs) transduce extracellular signals into discrete intracellular signals that regulate cell, tissue, and organ system function. They are the targets of approximately half of all therapeutic drugs. The beta-2-adrenoceptor (?2AR) is a GPCR and is targeted by beta-agonists in the treatment and prophylaxis of asthma. However, chronic use of ?-agonists can result in loss of its bronchoprotective effects, loss of disease control, and even mortality. Despite the limitation, relatively little progress has been made in asthma treatment. EP2/4 receptors, which are stimulated by prostaglandin E2 (PGE2), belong to the same subclass of GPCRs and have recently emerged as a potential therapeutic target in asthma. Protein kinase A or PKA, is a key effector of both of these GPCRs. However the signaling from these two GPCRs results in activated PKA which emanates through spatially distinct areas, and results in qualitatively distinct outcomes. The outlined proposal for this F32 fellowship is aided by the recent development of cutting edge tools and approaches, and represents a unique opportunity for training in airway cell biology relevant to obstructive lung diseases. Aim 1. Characterize differential PKA-dependent signaling in airway epithelial cells, and mediating mechanisms by beta-agonists and EP receptor subtype agonists. Aim 2. Demonstrate the dependence of beta-agonist and EP receptor agonist regulation of epithelial cells functions on compartmentalized signaling, and PKA. In aim 1, we will employ newly developed molecular and genetic tools in murine and human airway epithelial cultures to demonstrate that differential regulation of PKA signaling occurs in part due to compartmentalization of signaling elements. In aim 2, we will characterize the PKA-dependent regulation of gene regulation and cytokine production by different beta-agonists, PGE2, and EP subtype selective agonists in cells subject to 2 different strategies of PKA inhibition.