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

基本信息

批准号：
10654729
负责人：
Xiaoqiao Xie
金额：
$ 34.21万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目摘要/摘要我们对外围GFAP+ GliA如何调节感觉神经元活动的知识有很大的差距以及它们参与初级传入敏化。缺乏对外围神经胶质作用的理解细胞，主要是由于我们无法选择性地扰动信号传导途径在体内，在制定研究神经胶质的创造性和有效策略方面存在着重要的障碍慢性疾病的贡献。该项目的长期目标是靶向GFAP+卫星神经胶质细胞（SGC）用于预防和治疗周围敏化的基因疗法。该提议的目的是确定感觉神经节中SGC-Neuron相互作用的信号通路，以及表征内脏疼痛和膀胱涉及的感觉SGC信号传导的翻译体变化功能障碍。在慢性疼痛的背景下，有强烈的初步数据和过去的调查结果导致中心假设是，SGC中的GQ-GPCR信号有效地降低了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特定目的测试：1）检验感觉卫星Glial GQ-GPCR信号传导的假设在生理条件和炎症中降低膀胱传入敏感性并改变排尿诱发内脏疼痛和膀胱过度活动模型； 2）确定卫星胶质GQ-之间的分子联系 GPCR激活并降低了感觉神经元兴奋性； 3）发现感觉卫星的变化炎症引起的骨盆疼痛的发作和慢性期间的神经胶质翻译组道症状（LUTS）。在第一个目标下，外围GFAP+ GLIA中有针对性和选择性基因操纵将利用研究SGC在膀胱传入的生理和病理调节中的作用兴奋性。在第二个目标中，SGC-Neuron相互作用的细胞和分子机制将使用类似于研究CNS神经胶质神经元的方法在感觉神经节植体中识别原位相互作用。将在体内进行其他实验，以测试靶向的治疗潜力确定的信号通路可缓解此目的的内脏疼痛和膀胱过度活动。在第三目的，将采用陷阱技术来确定感觉SGC Translatome的变化作为炎症引起的膀胱过度活动和骨盆疼痛是一种无偏见的方式。拟议的研究是意义重大，因为1）它展示了一种选择性激活周围的新药物遗传学方法 Glia In Vivo，在神经艺术学研究中受益于更广泛的研究社区； 2）预计将填充知识差距在膀胱功能的神经胶质调制上，这是一个完全未开发的研究领域治疗潜力； 3）它为随后的临床前和临床试验提供了第一条证据靶向卫星神经胶质细胞和外周腺苷受体治疗骨盆疼痛； 4）在生理和疾病期间对周围神经胶质的特定子集进行遗传分析的基础。