Purinergic G protein signal integration in nociceptors

伤害感受器中的嘌呤能 G 蛋白信号整合

基本信息

批准号：
9049508
负责人：
DEREK C MOLLIVER
金额：
$ 27.85万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9049508
关键词：
ADRBK1 gene ADRBK2 gene Absence of pain sensation Acute Acute Pain Address Adenosine Diphosphate Adenylate Cyclase Adverse effects Affect Afferent Neurons Agonist American Analgesics Arrestins Binding Carrageenan Cells Chronic inflammatory pain Clinical Consumption Coupled Cyclic AMP Development Dose-Limiting Down-Regulation Family Family member Forskolin G protein coupled receptor kinase G-Protein-Coupled Receptors GTP-Binding Proteins Guanine Nucleotide Exchange Factors HSP 90 inhibition Health Healthcare Heat-Shock Proteins 90 Hyperalgesia Hypersensitivity Image In Vitro Inflammation Inflammatory Injection of therapeutic agent Injury Interleukin-1 Intractable Pain Laboratories Measures Mechanics Mediating Modeling Molecular Mus Neurons Nociception Nociceptive Stimulus Nociceptors Nucleotides Opioid Receptor Pain Pathway interactions Perception Peripheral Peripheral Nervous System Phosphotransferases Play Population Process Productivity Protein Kinase Quality of life Receptor Inhibition Receptor Signaling Regulation Reporting Research Resolution Role Signal Transduction Signaling Molecule Spinal Ganglia Stimulus System TRPV1 gene Testing Therapeutic Intervention Time Wild Type Mouse chronic pain cost differential expression improved in vivo inflammatory pain novel novel strategies protein kinase C epsilon ratiometric receptor receptor coupling receptor function research study response transmission process voltage

项目摘要

DESCRIPTION (provided by applicant): Chronic pain affects more than 50 million Americans per year, resulting in extraordinary personal and societal costs in diminished quality of life, los productivity and health care consumption. Improved treatments of acute and chronic pain conditions require a thorough understanding of the processes underlying the transmission and perception of painful stimuli. Discovery of the molecular and cellular mechanisms underlying acute and chronic pain is critical to the development of new treatments, particularly in mechanisms regulating the transition from acute to chronic pain. Recent studies from our laboratory have identified an endogenous analgesic mechanism that is present in peripheral sensory neurons conveying pain and is mediated by G protein-coupled receptors (GPCRs) for adenosine diphosphate (ADP). This project will investigate the role of ADP receptors signaling through Gi/o in hyperalgesia resulting from inflammatory injury, the regulation of P2Y signaling by GPCR kinases GRK2 and GRK3 during hyperalgesia, and will explore the hypothesis that these receptors are highly effective in ameliorating hyperalgesia mediated by adenylyl cyclase, a fundamental component of inflammatory pain. Specific Aim 1 will investigate the distribution of GRK2 and GRK3 in dorsal root ganglion (DRG) neurons and their regulation of P2Y signaling in vitro. Specific Aim 2 will determine whether GRK2 and GRK3 are co-regulated in the setting of inflammatory injury, and will examine the impact of altered GRK signaling on P2Y receptor inhibition of adenylyl cyclase using real-time cAMP imaging in vitro. Specific Aim 3 will determine the extent to which changes in the regulation of P2Y signaling contribute to the resolution of inflammatory hyperalgesia in vivo and whether manipulation of these pathways may provide a novel approach to the treatment of inflammatory pain. This proposal will examine the value of Gi/o-coupled P2Y receptors as targets for novel analgesic drugs, and will advance our understanding of fundamental mechanisms regulating GPCR function and nociceptive processing in the peripheral nervous system.

描述（由申请人提供）：慢性疼痛每年影响超过 5000 万美国人，导致生活质量下降、生产力下降和医疗保健消费等方面造成巨大的个人和社会成本。改善急性和慢性疼痛的治疗需要彻底了解疼痛刺激的传递和感知过程。急性和慢性疼痛背后的分子和细胞机制的发现对于新疗法的开发至关重要，特别是在调节急性疼痛向慢性疼痛转变的机制方面。我们实验室最近的研究发现，外周感觉神经元中存在一种内源性镇痛机制，可传递疼痛，并由二磷酸腺苷 (ADP) 的 G 蛋白偶联受体 (GPCR) 介导。该项目将研究通过 Gi/o 的 ADP 受体信号传导在炎症损伤引起的痛觉过敏中的作用、痛觉过敏期间 GPCR 激酶 GRK2 和 GRK3 对 P2Y 信号传导的调节，并将探讨这些受体在改善痛觉过敏介导的痛觉过敏方面非常有效的假设。腺苷酸环化酶是炎症性疼痛的基本成分。具体目标 1 将研究 GRK2 和 GRK3 在背根神经节 (DRG) 神经元中的分布及其对 P2Y 信号传导的体外调节。具体目标 2 将确定 GRK2 和 GRK3 在炎症损伤的情况下是否受到共同调节，并将使用体外实时 cAMP 成像检查 GRK 信号传导改变对腺苷酸环化酶 P2Y 受体抑制的影响。具体目标 3 将确定 P2Y 信号传导调节的变化在多大程度上有助于解决体内炎症性痛觉过敏，以及这些通路的操纵是否可以提供治疗炎症性疼痛的新方法。该提案将检验 Gi/o 偶联 P2Y 受体作为新型镇痛药物靶点的价值，并将增进我们对调节 GPCR 功能和周围神经系统伤害感受处理的基本机制的理解。