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

描述(由申请人提供)：K08的目标是为H.Henry Lai博士提供紧张的、有指导的基础研究经验，以过渡到从监督研究到独立研究人员的职业生涯。黎博士是一位非常合格的候选人。他的长期职业目标是成为一名成功的泌尿科科学家，在实验室和临床之间进行创新，致力于神经病学和膀胱/排尿障碍的关键研究领域。他的背景和训练清楚地表明了他的潜力和对科学研究的承诺。赖博士从事长椅研究，并在发表基础科学论文(六篇第一作者论文)方面卓有成效。尽管他在膀胱生理学和药理学方面的扎实背景为他的成功奠定了基础，但随着赖博士继续开发他的独立项目，他意识到自己之前接触的行为疼痛研究和分子神经科学是不够的，他需要更多的实验室保护研究时间才能成功。黎博士提出了一个全面的职业发展计划，专门为他的个人需要量身定做。该计划建立在他与他的导师Robert Gereau博士现有的卓有成效的合作基础上。Gereau博士是分子和行为疼痛研究领域的国际知名权威。他在膀胱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，并指导许多学员变得独立和富有成效。他在指导方面的奉献精神和技巧为他赢得了华盛顿大学的最高荣誉。Lai博士和Gereau博士一起在这里生成了强大的初步数据，并共同发表了论文。赖博士的职业发展计划有许多优点，包括通过频繁的一对一互动与导师轻松接触，有针对性和结构化的教学计划，利用华盛顿大学庞大的CTSA资源，拥有一支敬业的职业顾问团队，他们都是成功的临床科学家，以及具有明确目标、里程碑和监控机制的计划。华盛顿大学和泌尿科职业发展的体制环境非常好。Andriole博士(泌尿外科主任)和Eberlein博士(外科主席)承诺他们的整个科室承诺为赖博士提供60%受保护的研究时间。赖博士已拥有实验室空间、设备、启动资金和人员，为他的研究提供便利。代谢性谷氨酸受体5(MGluR5)在膀胱痛中的作用研究建议：Gereau博士(Mentor)先前已经证明，脊髓背角的代谢性谷氨酸受体亚型5(MGluR5)及其下游信号转导靶点ERK1/2(细胞外信号调节激酶)的激活，增加了脊髓神经元的兴奋性，参与了躯体疼痛超敏和脊髓中枢敏化的发展。虽然脊髓mGluR5在躯体疼痛模型中的作用已经被研究，但它在膀胱痛超敏反应中的作用还知之甚少。本研究的目的是探讨脊髓mGluR5及其信号靶标ERK1/2在小鼠膀胱痛模型中枢敏感化发展中的作用。我们的初步数据显示，在膀胱痛的小鼠模型中，膀胱痛过敏的发展与脊髓ERK1/2的激活(磷酸化)有关。功能性阻断脊髓ERK1/2的激活可减弱扩张引起的膀胱伤害性感受。脊髓mGluR5的激活也使幼稚的膀胱对扩张敏感。全身抑制mGluR5可减轻由伤害性扩张和炎症引起的膀胱伤害性感觉。综上所述，初步结果表明，mGluR5和ERK1/2的激活对于充分表达膀胱痛过敏至关重要。我们推测，脊髓mGluR5的激活诱导了脊髓ERK1/2信号的下游激活，并参与了脊髓中枢敏化和膀胱痛模型中膀胱痛觉过敏的发展。以下具体目标将通过药理学和遗传学方法的组合来解决：目的1：在小鼠膀胱痛(环磷酰胺膀胱炎、细菌性膀胱炎)模型中，测试脊髓mGluR5调节膀胱痛敏的假设。目的：验证mGluR5通过脊髓ERK1/2信号通路和脊髓神经元兴奋性调节膀胱痛觉过敏的假说。膀胱痛的研究与间质性膀胱炎和膀胱炎等一系列泌尿外科疾病相关，具有临床意义。该建议通过研究中枢神经系统疼痛敏感化的分子通路，解决了膀胱疼痛研究中的一个主要空白。这项研究具有创新性，因为将从全新的角度在中枢神经系统水平上研究膀胱痛过敏症 多学科协作。该方法也为赖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.