Activating Peripheral Glia to Relieve Visceral Pain in Animal Models of Urological Chronic Pelvic Pain Syndrome (UCPPS)

激活外周神经胶质细胞以缓解泌尿科慢性盆腔疼痛综合征 (UCPPS) 动物模型中的内脏疼痛

• 批准号: 10273491
• 负责人: Xiaoqiao Xie
• 金额: $ 32.74万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10273491
• 关键词: Absence of pain sensation; Adenosine A1 Receptor; Adenosine Triphosphate; Afferent Neurons; Affinity Chromatography; American; Analgesics; Animal Model; Bladder; Bladder Control; Bladder Dysfunction; Chemicals; Chronic; Chronic Disease; Chronic Phase; Clinical Trials; Communities; Data; Dependence; Disease; Dose; Elements; Frequencies; Functional disorder; G Protein-Coupled Receptor Signaling; G alpha q Protein; G-Protein-Coupled Receptors; Glial Fibrillary Acidic Protein; Goals; Hyperalgesia; Hypersensitivity; In Situ; Increased frequency of micturition; Individual; Inflammation; Injury; Knowledge; Link; Maintenance; Mechanics; Messenger RNA; Modeling; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nerve Degeneration; Neuroglia; Neurons; Nociception; Overactive Bladder; Pathogenesis; Pathologic; Patients; Pelvic Pain; Pelvis; Peripheral; Pharmacogenetics; Pharmacotherapy; Physiological; Physiology; Protocols documentation; Purinergic P1 Receptors; Regulation; Reporting; Research; Rewards; Ribosomes; Role; Sensory; Sensory Ganglia; Signal Pathway; Signal Transduction; Symptoms; Technology; Testing; Therapeutic; Time; Translating; Urination; Urine; Urology; Visceral; Visceral pain; adenosine receptor activation; chronic pain; chronic painful condition; chronic pelvic pain; design; effective therapy; experience; experimental study; gastrointestinal; gene therapy; genetic analysis; genetic manipulation; high reward; high risk; in vivo; lower urinary tract symptoms; micturition urgency; mouse model; neuronal excitability; neuroregulation; neurotransmission; novel therapeutics; pain behavior; preclinical trial; prevent; receptor; reduce symptoms; response; therapeutic evaluation; therapeutic target; translatome; treatment strategy; urologic chronic pelvic pain syndrome

PROJECT SUMMARY/ABSTRACT There are significant gaps in our knowledge of how peripheral GFAP+ glia regulate sensory neuronal activity and their involvement in primary afferent sensitization. The lack of understanding of the roles of peripheral glial cells, mainly due to our inability of selectively perturbing signaling pathways in subpopulations of peripheral glia in vivo, presents an important obstacle in developing creative and effective strategies for investigating glial contribution in chronic diseases. The long-term goal of this project is to target GFAP+ satellite glial cells (SGCs) for gene therapies for preventing and treating peripheral sensitization. The objective of this proposal is to identify signaling pathways underlying SGC-neuron interaction in the sensory ganglia, as well as to characterize the translatome changes in sensory SGC signaling involved in visceral pain and bladder dysfunction. Strong preliminary data and past findings in sensory SGCs in the context of chronic pain led to the central hypothesis that Gq-GPCR signaling in SGCs potently decreases the excitability and activity in bladder- projecting sensory neurons and contributes to neural control of bladder functions. This hypothesis will be tested by pursuing three specific aims: 1) Test the hypothesis that sensory satellite glial Gq-GPCR signaling decreases bladder afferent sensitivity and alters micturition in physiological conditions and in inflammation- induced visceral pain and bladder overactivity model; 2) Identify the molecular link between satellite glial Gq- GPCR activation and decreased sensory neuronal excitability; and 3) Discover the changes in sensory satellite glial translatome during the onset and chronic phase of inflammation-induced pelvic pain and lower urinary tract symptoms (LUTS). Under the first aim, targeted and selective gene manipulation in peripheral GFAP+ glia will be utilized to study the role of SGCs in physiological and pathological regulation of bladder afferent excitability. In the second aim, the cellular and molecular mechanism underlying SGC-neuron interaction will be identified in sensory ganglia explants using approaches similar to those used in studying CNS glial-neuronal interactions in situ. Additional experiments will be performed in vivo to test the therapeutic potential of targeting the identified signaling pathway(s) for alleviating visceral pain and bladder overactivity in this aim. Under the third aim, TRAP technology will be employed to identify changes in sensory SGC translatome as a function of inflammation-induced bladder overactivity and pelvic painin a non-biased manner.The proposed research is significant because 1) it demonstrates a new pharmacogenetic approach for selectively activating peripheral glia in vivo, which benefits broader research community in Neuro-urology research; 2) it is expected to fill the knowledge gap on glial modulation of bladder function, a completely unexplored research field with high therapeutic potential; 3) it provides the first line of evidence for subsequent pre-clinical and clinical trials of targeting satellite glial cells and peripheral adenosine receptors in treating pelvic pain; and 4) it lays the groundwork for genetic analysis on specific subsets of peripheral glia during physiology and disease.

项目概要/摘要 我们对于外周 GFAP+ 神经胶质细胞如何调节感觉神经元活动的认识存在重大差距 及其参与初级传入敏化。对外周胶质细胞的作用缺乏了解 细胞，主要是由于我们无法选择性地干扰外周神经胶质细胞亚群中的信号通路 在体内，这对开发研究神经胶质细胞的创造性和有效策略提出了重要障碍 对慢性病的贡献。该项目的长期目标是针对 GFAP+ 卫星胶质细胞（SGC） 用于预防和治疗外周过敏的基因疗法。该提案的目的是 识别感觉神经节中 SGC-神经元相互作用的信号通路，以及 表征内脏疼痛和膀胱中涉及的感觉 SGC 信号传导的翻译组变化 功能障碍。强有力的初步数据和过去在慢性疼痛背景下感觉 SGC 的发现导致了 中心假设是 SGC 中的 Gq-GPCR 信号传导有效降低膀胱的兴奋性和活性 投射感觉神经元并有助于膀胱功能的神经控制。这个假设将是 通过追求三个具体目标进行测试：1）测试感觉卫星胶质细胞 Gq-GPCR 信号传导的假设 降低膀胱传入敏感性并改变生理条件和炎症中的排尿- 诱发内脏疼痛和膀胱过度活动模型； 2) 识别卫星胶质Gq-之间的分子联系 GPCR 激活并降低感觉神经元兴奋性； 3）发现感觉卫星的变化 炎症引起的盆腔疼痛和下尿路的发作和慢性阶段的神经胶质翻译组 肠道症状（LUTS）。第一个目标是外周 GFAP+ 神经胶质细胞的靶向和选择性基因操作 将用于研究SGC在膀胱传入生理和病理调节中的作用 兴奋性。在第二个目标中，SGC-神经元相互作用的细胞和分子机制将 使用类似于研究中枢神经系统胶质神经元的方法在感觉神经节外植体中进行鉴定 现场互动。将在体内进行额外的实验以测试靶向的治疗潜力 已确定的信号通路可用于缓解内脏疼痛和膀胱过度活动。下 第三个目标，TRAP 技术将用于识别感觉 SGC 翻译组的变化作为函数 以无偏见的方式研究炎症引起的膀胱过度活动和盆腔疼痛。拟议的研究是 意义重大，因为 1) 它展示了一种选择性激活外周血的新药物遗传学方法 体内神经胶质细胞，这有利于神经泌尿学研究领域更广泛的研究界； 2）预计将填补 神经胶质细胞调节膀胱功能的知识差距，这是一个完全未经探索的研究领域，具有很高的研究价值 治疗潜力； 3）为后续的临床前和临床试验提供第一线证据 靶向卫星胶质细胞和外周腺苷受体治疗盆腔疼痛； 4）它奠定了 为生理和疾病期间外周神经胶质细胞特定亚群的遗传分析奠定了基础。