THE ROLE OF METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLUR5) IN BLADDER PAIN

描述（由申请人提供）：本K 08的目标是为H.亨利赖与一个强烈的指导基础研究的经验，以桥梁从监督研究成功过渡到职业生涯作为一个独立的调查员。黎博士是一个非常合格的候选人。他的长期职业目标是成为一名成功的泌尿科医生-科学家，在实验室和诊所之间的界面进行创新，以解决神经泌尿学和膀胱/排尿疾病的关键研究领域。他的背景和训练清楚地表明了他对科学研究的潜力和承诺。赖博士从事实验室研究，并在发表基础科学论文方面卓有成效（六篇第一作者论文）。尽管他在膀胱生理学和药理学方面的扎实背景为成功奠定了基础，但随着赖博士继续开发他的独立项目，他意识到他之前对行为疼痛研究和分子神经科学的接触是不够的，他需要在实验室中获得额外的保护研究时间才能取得成功。黎博士提出了一个全面的职业发展计划，专门针对他的个人需求。这个计划是基于他与导师Robert Gereau博士现有的富有成效的合作。Gereau博士是分子和行为疼痛研究的国际知名权威。他在膀胱疼痛研究和中枢神经系统疼痛敏感化方面拥有独立的NIH资金，并指导了许多学员变得独立和富有成效。他的奉献精神和指导技巧为他赢得了华盛顿大学的最高荣誉。赖博士和Gereau博士共同在这里生成了强有力的初步数据，并共同发表。赖博士的职业发展计划有许多优点，包括容易获得导师与频繁的一对一互动，重点和结构化的教学计划，利用大量的CTSA资源在华盛顿大学，一个专门的职业顾问团队谁都是成功的临床科学家，以及一个明确的目标，里程碑和监测机制的计划。在华盛顿大学和泌尿科的职业发展的制度环境是杰出的。Andriole博士（泌尿科主任）和Eberlein博士（外科主任）已承诺他们的整个部门的承诺，为赖博士提供60%的保护研究时间。赖博士已经有一个现有的实验室空间，设备，启动资金和人员，以促进他的研究。代谢型谷氨酸受体5（mGluR 5）在膀胱疼痛中的作用研究建议：Gereau博士（Mentor）先前已经表明，代谢型谷氨酸受体亚型5（mGluR 5）及其下游信号传导靶点ERK 1/2的激活（细胞外信号调节激酶），在脊髓背角中，增加脊髓神经元的兴奋性，并有助于躯体疼痛超敏反应的发展，脊髓中枢敏感化虽然已经在躯体疼痛模型中研究了脊髓mGluR 5的作用，但对其在膀胱疼痛超敏反应发展中的作用知之甚少。本研究的目的是探讨脊髓mGluR 5及其信号转导靶点ERK 1/2在膀胱疼痛小鼠模型中枢致敏中的作用。我们的初步数据表明，在膀胱疼痛的小鼠模型中，膀胱痛觉过敏的发展与脊髓ERK 1/2的激活（磷酸化）有关。脊髓ERK 1/2激活的功能性阻断减弱扩张诱发的膀胱伤害性感受。脊髓mGluR 5的激活也使幼稚膀胱对膨胀敏感。全身性抑制mGluR 5减弱由伤害性膨胀和炎症诱导的膀胱伤害性感受。总之，初步结果表明，mGluR 5和ERK 1/2激活对于膀胱疼痛超敏反应的充分表达至关重要。我们假设脊髓mGluR 5的激活诱导脊髓ERK 1/2信号传导的下游激活，并有助于脊髓中枢敏化和膀胱疼痛小鼠模型中膀胱痛觉过敏的发展。将使用药理学和遗传学方法的组合来解决以下具体目的：目的1：检验脊髓mGluR 5调节膀胱疼痛小鼠模型（环磷酰胺膀胱炎、细菌性膀胱炎）中膀胱痛觉过敏的假设。 目的2：验证mGluR 5通过脊髓ERK 1/2信号通路和脊髓神经元兴奋性调节膀胱痛觉过敏的假说。膀胱疼痛的研究与间质性膀胱炎和膀胱感染等泌尿系统疾病有关，具有临床意义。该建议通过研究中枢神经系统疼痛致敏的分子途径来解决膀胱疼痛研究中的一个主要空白。这项研究是创新的，因为膀胱疼痛超敏反应将从一个全新的角度在中枢神经系统水平进行研究， 多学科合作。该方法还为黎博士提供了一个最佳的培训平台，让他学习分子/行为疼痛研究和神经科学方面的新专业知识，成为一名独立的研究人员。

DESCRIPTION (provided by applicant): The goal of this K08 is to provide Dr. H. Henry Lai with an intense mentored basic research experience to bridge a successful transition from supervised research to a career as an independent investigator. Dr. Lai is an exceptionally qualified candidate. His long-term career goal is to become a successful urologist- scientist, innovating at the interface between the laboratory and the clinic, to address critical research areas in neurourology and bladder/voiding disorders. His background and training demonstrated unequivocally his potential and commitment to scientific research. Dr. Lai has engaged in bench research and has been productive in publishing basic science papers (six first-authored papers). Even though his solid background in bladder physiology and pharmacology has laid the foundation of success, as Dr. Lai continues to develop his independent program, he realized that his previous exposure to behavioral pain research and molecular neuroscience is inadequate, and he would need additional protected research time in the lab to succeed. Dr. Lai has proposed a comprehensive career development plan that is specifically tailored to his individual needs. This plan is anchored on his existing and productive collaboration with his Mentor, Dr. Robert Gereau, Ph.D. Dr. Gereau is an internationally renowned authority in molecular and behavioral pain research. He has independent NIH funding in bladder pain research and CNS pain sensitization, and has mentored many trainees to become independent and productive. His devotion and skill in mentoring won him the highest honor at Washington University. Together, Drs. Lai and Gereau have generated strong preliminary data here and have published together. There are many strengths of Dr. Lai's career development plan, including easy accessibility to the Mentor with frequent one-on-one interaction, a focused and structured didactic program, utilization of the vast CTSA resources at Washington University, a devoted team of Career Advisors who are all successful clinician-scientists, and a plan with well defined objectives, milestones, and monitoring mechanisms. The institutional environment for career development at Washington University and in the Division of Urology is outstanding. Dr. Andriole (Chief of Urology) and Dr. Eberlein (Chairman of Surgery) have pledged their full department commitment to provide Dr. Lai with 60% protected research time. Dr. Lai already has an existing laboratory space, equipments, start-up funds, and personnel to facilitate his research. The role of metabotropic glutamate receptor 5 (mGluR5) in bladder pain Research Proposal: Dr. Gereau (Mentor) has previously shown that activation of metabotropic glutamate receptor subtype 5 (mGluR5) and its downstream signaling targets, ERK1/2 (extracellular signal-regulated kinases), in spinal cord dorsal horn increases the excitability of the spinal neurons and contributes to the development of somatic pain hypersensitivity and spinal central sensitization. While the roles of spinal mGluR5 have been studied in somatic pain models, its role in the development of bladder pain hypersensitivity is poorly understood. The objective of this proposal is to investigate the roles of spinal mGluR5 and its signaling targets ERK1/2 in the development of central sensitization in mouse models of bladder pain. Our preliminary data show that in a mouse model of bladder pain, development of bladder hyperalgesia is associated with robust spinal cord ERK1/2 activation (phosphorylation). Functional blockade of spinal ERK1/2 activation attenuates the distention-evoked bladder nociception. Activation of spinal mGluR5 also sensitizes the naive bladder to distention. Systemic inhibition of mGluR5 attenuates the bladder nociception induced by noxious distention and inflammation. Together, preliminary results indicate that mGluR5 and ERK1/2 activation for critical for full expression of bladder pain hypersensitivity. We hypothesize that activation of spinal mGluR5 induces downstream activation of spinal ERK1/2 signaling, and contributes to spinal central sensitization and the development of bladder hyperalgesia in mouse models of bladder pain. The following specific aims will be addressed using a combination of pharmacologic and genetic approaches: Aim 1: To test the hypothesis that spinal mGluR5 modulates bladder hyperalgesia in mouse models of bladder pain (cyclophosphamide cystitis, bacterial cystitis). Aim 2: To test the hypothesis that mGluR5 modulates bladder hyperalgesia via spinal ERK1/2 signaling and by modulating spinal neuronal excitability. The study of bladder pain has clinical significance in relation to a number of urologic conditions such as interstitial cystitis and bladder infection. Ths proposal addresses a major gap in bladder pain research by investigating the molecular pathways that underlie CNS pain sensitization. The research is innovative because bladder pain hypersensitivity will be investigated from an entirely new perspective at the level of the CNS with multidisciplinary collaboration. The approach also provides an optimal training platform for Dr. Lai to learn new expertise in molecular/behavioral pain research and neuroscience to become an independent researcher.