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Compartmentalized signaling and crosstalk in airway myocytes

气道肌细胞中的区室化信号传导和串扰

基本信息

批准号：
10718208
负责人：
RENNOLDS S OSTROM
金额：
$ 58.16万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718208
关键词：
A kinase anchoring protein Adenylate Cyclase Adult Affect Agonist Arrestins Asthma Basic Science Biology Biosensor Cell Nucleus Cell Separation Cell membrane Cell physiology Cells Characteristics Child Chronic Disease Clinical Complement Coughing Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytosol Data Disparate Dissociation EP4 receptor Elements Exhibits Foundations G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors GTP-Binding Proteins Goals Grant Heterotrimeric GTP-Binding Proteins Human Image Imaging Techniques Integral Membrane Protein Intracellular Membranes Kinetics Knowledge Link Location Measures Mediating Membrane Microdomains Methodology Molecular Biology Muscle Cells Muscle Contraction Muscle function Outcome Pathway interactions Phospholipase C Phosphoproteins Phosphorylation Phosphotransferases Physiological Post-Translational Protein Processing Protein Isoforms Proteins Proteome Receptor Signaling Regulation Relaxation Role Second Messenger Systems Shapes Shortness of Breath Signal Pathway Signal Transduction Smooth Muscle Myocytes Specificity Symptoms System Testing Visualization Wheezing Work airway hyperresponsiveness airway inflammation airway remodeling asthmatic design experimental study genetic regulatory protein grasp imaging approach insight knock-down mathematical model migration new therapeutic target novel overexpression preservation protein protein interaction receptor respiratory smooth muscle response spatiotemporal stoichiometry subcellular targeting tool

项目摘要

PROJECT SUMMARY/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.

项目总结/摘要这项基础科学基金旨在确定生理相关的基本机制，细胞控制信号的亚细胞位置，以优化该信号对细胞功能的影响。我们提出基于我们多样化的调查团队最近的发现，描述了3种不同的GS偶联受体如何在气道平滑肌（ASM）细胞--E2 AR、EP 2和EP 4受体--的信号是区室化的在细胞内调节重要的ASM细胞功能。目标1将采用新的成像方法来描绘每个受体cAMP/PKA信号传导的时空特征，并证明了这是如何划分的信号传导是由AKAP和PDE同种型的受体特异性互补物以及竞争性共激活的Gq偶联受体。AIM 1还将采用多个亚细胞靶向生物传感器来表征每个受体从细胞内膜隔室发出信号的能力。目标2将评估这些不同的受体产生独特的磷酸化蛋白质组签名，以及如何操纵机制，形成局部cAMP/PKA信号调节这些特征。目标3将确定机制如何决定ASM cAMP和ASM蛋白质组的时空特征影响Gs-coupled GPCR调控 ASM收缩、迁移和合成功能。拟议的研究将为以下方面奠定基础：以方法进步和知识的形式理解划分信号 Gs偶联受体如何利用不同的信号传导机制，功能效应。从翻译的角度来看，我们的发现将构成一个关键的基础科学基础用于开发靶向信号室机制的新药，最容易应用于更好的控制哮喘的特征，如气道高反应性、气道重塑，炎症