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，导致生活质量降低，LOS生产力和医疗保健消费的非同寻常的个人和社会成本。改善急性和慢性疼痛状况的治疗需要彻底了解疼痛刺激的传播和感知的过程。发现急性和慢性疼痛为基础的分子和细胞机制的发现对于新疗法的发展至关重要，特别是在调节从急性到慢性疼痛过渡的机制中。我们实验室的最新研究确定了一种内源性镇痛机制，该机制存在于外周感觉神经元中，可传达疼痛，并由G蛋白偶联受体（GPCR）介导用于二磷酸腺苷（ADP）。该项目将研究通过炎症损伤引起的ADP受体信号传导在炎症性损伤，GPCR激酶GRK2和GRK3期间对P2Y信号传导导致的高温过敏中的作用，并将探索这些受体在增强疗效的高温介导的腺苷糖酶促进的蛋白酶乳化酶，一种依克酶的组合，并探索这些受体在增强效率上有效的假设。具体目标1将研究在背根神经（DRG）神经元中GRK2和GRK3的分布，并在体外调节P2Y信号传导。具体的目标2将确定GRK2和GRK3是否在炎症损伤的情况下共同调节，并将检查改变GRK信号对P2Y受体抑制腺苷酸环化酶的影响，并使用体外实时cAMP成像。具体目标3将确定P2Y信号传导调节的变化的程度有助于在体内解决炎症性痛觉过敏，以及对这些途径的操纵是否可以为治疗炎症性疼痛的治疗提供新的方法。该建议将研究GI/O偶联P2Y受体作为新型镇痛药的靶标的价值，并将提高我们对调节GPCR功能和伤害感受性处理的基本机制的理解。