It is now appreciated the cell often compartmentalizes signaling, presumably as a means of expanding its diversity of control over how it functions. Importantly, this complexity in signaling expands the number of druggable targets, and the ability to modulate specific cell functions linked to compartmentalized signaling. Our recent data suggest that different members of the GPCR subfamily of Gs-coupled receptors exhibit distinct compartmentalized signaling in ASM, affecting both the quantitative and qualitative nature of the signaling, which may explain the receptor?s differential capacity to regulate ASM functions. Studies in this proposal will therefore test the hypothesis that distinct complements of signaling effectors and regulators serve to compartmentalize signaling in ASM cells, resulting in differential ability of ?2AR and prostaglandin E (EP) receptors to regulate ASM contraction. This hypothesis will be tested in 3 Specific Aims.
Aim 1 will employ cutting edge imaging, biochemical, proteomic, and molecular biology approaches to establish that ?2AR, EP2, and EP4 receptor signaling occurs in different cellular regions to produce quantitatively and qualitatively different outcomes.
In Aim 2 we will target multiple putative regulators of compartmentalized signaling to establish the mechanistic basis for the distinct signaling by each of the receptors.
In Aim 3 we will similarly target mechanisms of receptor compartmentalization in order to link the compartmentalized signaling of ?2AR, EP2 and EP4 receptors to differential regulation of ASM contraction. The basic science goal of these studies is to delineate mechanisms by which the cell compartmentalizes signals for different Gs-coupled receptors in a relevant primary cell type, and link this regulation to changes in cell function. The translational goal is to identify new therapeutic targets and strategies, enabling a greater number of more selective and efficacious approaches to managing the asthma phenotype.
In order to better understand the basis for the effectiveness of asthma drugs, we propose to characterize previously undefined signaling events mediated by receptors in airway smooth muscle. Whereas previous studies have analyzed global signaling events in these cells, we will assess localized, compartmentalized signaling events and how such compartmentalization is regulated. These studies will reveal an unappreciated depth of signaling complexity mediated by asthma drugs, thereby providing a basis for both new drug targets and improved drug discovery approaches for obstructive lung diseases.
Showing the most recent 10 out of 24 publications
