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

代谢型谷氨酸受体 5 (MGLUR5) 在膀胱疼痛中的作用

• 批准号: 8875673
• 负责人: Hing Hung Henry Lai
• 金额: $ 13.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875673
• 关键词: Abdomen; Acute; Address; Afferent Neurons; Agonist; Animals; Area; Attention; Attenuated; Basic Science; Behavioral; Bladder; Cell physiology; Chairperson; Chemicals; Chronic; Clinic; Collaborations; Complement; Cyclophosphamide; Cystitis; Data; Development; Development Plans; Disease; Doctor of Philosophy; Environment; Equipment; Exposure to; Filament; Foundations; Funding; GRM5 gene; Genetic; Goals; Health; Human Resources; Hyperalgesia; Hypersensitivity; Individual; Infective cystitis; Inflammation; Inflammatory; Interdisciplinary Study; Interstitial Cystitis; Knockout Mice; Laboratories; Learning; MAPK1 gene; MAPK3 gene; MEKs; Mechanics; Mediating; Mentors; Metabotropic Glutamate Receptors; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; Mus; Nervous system structure; Neuraxis; Neuronal Plasticity; Neurons; Neurosciences; Nociception; Nociceptors; Operative Surgical Procedures; Pain; Pain Research; Paper; Pathway interactions; Patients; Peripheral; Pharmacology; Phosphorylation; Physicians' Offices; Physiology; Play; Pre-Clinical Model; Prevalence; Process; Protein Isoforms; Publishing; Qualifying; Research; Research Personnel; Research Proposals; Resources; Role; Saline; Scientist; Sensory; Signal Transduction; Solid; Spinal; Spinal Cord; Spinal cord posterior horn; Structure; Symptoms; Tactile; Testing; Time; Training; United States National Institutes of Health; Universities; Urinary tract infection; Urologist; Urology; Uropathogenic E. coli; Urothelium; Visceral; Visceral pain; Washington; Western Blotting; Whole-Cell Recordings; Wild Type Mouse; allodynia; authority; behavior observation; bladder pain; burden of illness; career; career development; central sensitization; clinically significant; effective therapy; experience; genetic approach; inhibitor/antagonist; innovation; metabotropic glutamate receptor 5; mouse model; neuronal excitability; programs; research study; response; skills; success; urologic

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.

描述（由申请人提供）：这个K08的目标是为H. Henry Lai博士提供密集的基础研究指导经验，以成功地从监督研究过渡到作为独立研究者的职业生涯。赖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医生-科学家，在实验室和临床之间进行创新，以解决神经病学和膀胱/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，并多次发表基础科学论文（六篇第一作者论文）。尽管他在膀胱生理学和药理学方面的坚实背景为成功奠定了基础，但随着赖博士继续发展他的独立项目，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，他需要在实验室里额外的受保护的研究时间才能成功。赖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。这个计划是建立在他与他的导师Robert Gereau博士的现有和富有成效的合作基础上的。Robert Gereau博士是国际知名的分子和行为疼痛研究权威。他在膀胱疼痛研究和中枢神经系统疼痛敏化方面拥有独立的NIH资助，并指导了许多学员成为独立和富有成效的人。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。在一起,Drs。Lai和Gereau在这里获得了强有力的初步数据，并一起发表了论文。赖博士的职业发展计划有许多优点，包括与导师进行频繁的一对一互动，重点突出和结构化的教学计划，利用华盛顿大学CTSA的大量资源，一支由成功的临床科学家组成的专业职业顾问团队，以及一个具有明确目标、里程碑和监督机制的计划。华盛顿大学泌尿科的制度环境非常适合职业发展。Andriole医生（泌尿科主任）和Eberlein医生（外科主任）已承诺为赖医生提供60%受保护的研究时间。赖博士已经拥有现有的实验室空间、设备、启动资金和人员来促进他的研究。代谢性谷氨酸受体5 （mGluR5）在膀胱疼痛中的作用研究建议：Gereau博士（Mentor）之前已经表明，脊髓背角中代谢性谷氨酸受体亚型5 （mGluR5）及其下游信号靶点ERK1/2（细胞外信号调节激酶）的激活会增加脊髓神经元的兴奋性，并有助于躯体疼痛超敏性和脊髓中枢敏化的发展。虽然已经研究了脊髓mGluR5在躯体疼痛模型中的作用，但其在膀胱疼痛超敏反应发展中的作用尚不清楚。本研究旨在探讨脊髓mGluR5及其信号靶点ERK1/2在膀胱疼痛小鼠模型中枢致敏过程中的作用。我们的初步数据显示，在膀胱疼痛的小鼠模型中，膀胱痛觉过敏的发展与脊髓ERK1/2的激活（磷酸化）有关。脊髓ERK1/2激活的功能阻断可减弱扩张引起的膀胱痛觉。脊髓mGluR5的激活也使幼稚膀胱对膨胀敏感。全身抑制mGluR5可减轻有害肿胀和炎症引起的膀胱痛觉。总之，初步结果表明mGluR5和ERK1/2的激活对于膀胱疼痛超敏反应的完全表达至关重要。我们假设脊髓mGluR5的激活诱导了脊髓ERK1/2信号的下游激活，并在膀胱疼痛小鼠模型中参与脊髓中枢致敏和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结合来解决：目的1：在膀胱疼痛（环磷酰胺性膀胱炎，细菌性膀胱炎）的小鼠模型中，验证脊髓mGluR5调节膀胱痛症的假设。目的2：验证mGluR5通过脊髓ERK1/2信号通路和调节脊髓神经元兴奋性调节膀胱痛觉过敏的假说。膀胱疼痛的研究与许多泌尿系统疾病如间质性膀胱炎和膀胱感染有关，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，解决了膀胱疼痛研究的主要空白。这项研究具有创新性，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的水平上进行研究