Purinergic G protein signal integration in nociceptors

伤害感受器中的嘌呤能 G 蛋白信号整合

• 批准号: 8838952
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838952
• 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 Genes; 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; improved; in vivo; inflammatory pain; novel; novel strategies; protein kinase C epsilon; ratiometric; receptor; receptor coupling; receptor function; research study; response; transmission process; voltage

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5000多万美国人，导致个人和社会付出巨大代价，导致生活质量下降、生产力下降和医疗保健消费。改善对急性和慢性疼痛状况的治疗需要对疼痛刺激的传递和感知的基本过程有彻底的了解。发现急性和慢性疼痛的分子和细胞机制对于开发新的治疗方法至关重要，特别是在调节从急性疼痛到慢性疼痛的机制方面。最近我们实验室的研究发现了一种内源性镇痛机制，这种机制存在于传递疼痛的外周感觉神经元中，并由腺苷二磷酸(ADP)的G蛋白偶联受体(GPCRs)介导。本课题将研究ADP受体通过Gi/o在炎性损伤所致痛敏中的作用，以及GPCRK2和GRK3在痛敏过程中对P2Y信号的调节，并将探索这些受体在减轻炎性疼痛的基本成分腺酰环化酶介导的痛敏中的高效假说。目的1研究GRK2和GRK3在体外培养的背根神经节(DRG)神经元中的分布及其对P2Y信号的调控。特异性目标2将确定GRK2和GRK3是否在炎症损伤的背景下共同调节，并将在体外利用实时cAMP成像检测改变的GRK信号对P2Y受体抑制腺苷环化酶的影响。具体目标3将确定在体内P2Y信号调节的改变在多大程度上有助于炎性痛觉过敏的解决，以及这些途径的操纵是否可能为炎性疼痛的治疗提供一种新的方法。这一建议将考察Gi/o偶联的P2Y受体作为新型止痛药靶点的价值，并将促进我们对调控GPCR功能和外周神经系统伤害性处理的基本机制的理解。