Compartmentalized signaling and crosstalk in airway myocytes

Active Project Grant Awarded Last action

Award ID
R01HL169522
Recipient
Awarding agency
Obligated
$2,223,158

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 83% complete
Place of performance
Mobile, AL 36688, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
This basic science grant seeks to determine fundamental mechanisms as to how a physiologically relevant cell controls the subcellular location of a signal to optimize the effect of that signal on cell function. We propose to build on recent findings by our diverse investigative team to delineate how 3 different GS-coupled receptors in airway smooth muscle (ASM) cells - the 2AR, EP2, and EP4 receptors- have their signals compartmentalized within the cell to regulate important ASM cell functions. Aim 1 will employ novel imaging approaches to delineate spatiotemporal features of camp/PKA signaling by each receptor and demonstrate how this compartmentalized signaling is shaped by receptor-specific complements of akap and PDE isoforms, and by the competing CO- activated GQ-coupled receptor. Aim 1 will also employ multiple subcellular-targeted biosensors to characterize the capacity of each receptor to signal from intracellular membrane compartments. Aim 2 will assess how these different receptors generate unique phosphoproteome signatures, and how manipulating the mechanisms shaping localized camp/PKA signaling regulates these signatures. Aim 3 will establish how the mechanisms dictating spatiotemporal features of ASM camp and the ASM proteome affect GS-coupled gpcr regulation of ASM contraction, migration, and synthetic functions. The proposed studies will provide a foundation for understanding compartmentalized signaling in the form of both methodological advances and the knowledge gained in how GS-coupled receptors employ distinct signaling mechanisms to render efficient and specific functional effects. From a translational perspective, our findings will constitute a critical basic science foundation for developing new drugs that target mechanisms of signaling compartments, most readily applied to better control asthma features such as airway hyperresponsiveness, airway remodeling, and possibly airway inflammation.

Transactions

Action Obligated Date
Amendment $543,494
Amendment $554,585
Amendment $543,494
Original award $581,585

Subawards

Subrecipient Amount Awarded
Thomas Jefferson University Dr. Penn will provide oversight of Aim 3 studies assessing the effects of multiple strategies targeting mechanisms of signaling compartmentalization on… $191,100
Chapman University We will use tandem mass tag (iTRAQ) to identify and quantify all phosphopeptides. iTRAQ uses isobaric reagents that are reactive with the primary amines of… $167,580
Chapman University We will use machine learning to interpret the phosphopeptide signatures and decipher the compartments that are regulated. This approach will allow comparison of… $171,000
Thomas Jefferson University Dr. Penn will provide oversight of Aim 3 studies assessing the effects of multiple strategies targeting mechanisms of signaling compartmentalization on… $195,000
Thomas Jefferson University Dr. Penn will provide oversight of Aim 3 studies assessing the effects of multiple strategies targeting mechanisms of signaling compartmentalization on… $191,340
Chapman University Almost nothing is known about how signaling phosphoproteins downstream of PKA and Epac are stratified between compartments. To address this critical gap in… $167,340

Quick answers

Who received award R01HL169522?

R01HL169522 was awarded to University Of South Alabama by National Heart Lung and Blood Institute (National Institutes of Health) on July 1, 2023.

How much is award R01HL169522 worth?

$2,223,158 has been obligated on R01HL169522.

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