Afferent Hyperactivity Mechanisms in Overactive Bladder Syndrome

 描述(由申请者提供)：这一职业发展奖的首要目标是提供一个全面的培训计划，为雷诺兹博士独立资助的临床研究生涯做好准备，专注于膀胱过度活动症(OAB)患者的治疗结果。雷诺兹博士是一名泌尿外科助理教授和委员会认证的泌尿科医生，接受过女性骨盆医学和重建外科(FPMRS)的临床专科奖学金培训，并拥有医疗服务和结果研究(公共卫生硕士，公共卫生硕士)的高级学位。雷诺兹博士的近期目标是在临床和翻译研究技术方面获得更多的专业知识，同时继续对潜在的传入神经或内脏多动(OAB的一种拟议机制)的临床表现和治疗效果进行富有成效的研究。这一奖项将允许他通过正规的研究生水平的课程学习和5年的指导研究保护来实现这一目标。雷诺兹博士已经组建了一个多学科指导团队来帮助实现这一目标。他的主要导师是Stephen Bruehl博士，他在慢性疼痛和内脏过敏机制的高影响临床和翻译研究方面拥有良好的记录。他的职业发展还得益于两位合作导师：David Penson，医学博士，公共卫生硕士，是一名泌尿科医生和经验丰富的研究员，在前列腺癌生活质量和存活率的比较有效性和结果研究方面拥有专业知识；Roger Dmochowski，医学博士，MMHC，是一名泌尿科医生，也是在过度活跃的膀胱和功能性膀胱疾病方面的国际公认专家。范德比尔特大学医学中心为研究和年轻研究人员的培训提供了丰富的环境，并通过临床和转化型科学家发展办公室对所有受指导的内科科学家进行集中监督，包括范德比尔特医生科学家发展计划，该计划为雷诺兹博士受保护的研究和职业发展活动提供资金。此外，作为范德比尔特卫生服务研究中心和外科质量和结果研究中心的成员，雷诺兹博士可以立即接触到研究人员、特邀演讲者和最先进的核心研究设施。他的长期目标是S成为一名独立资助的外科医生兼科学家，拥有独特的技能和培训，在一个将影响这种疾病患者护理的大型翻译OAB研究计划中架起翻译、临床和医疗服务研究的桥梁。这份提案中详细说明的强有力的指导、额外的培训和环境将使他最终实现这一目标。这项研究提案将研究脊髓介导的传入多动，特别是中枢敏化(CS)如何有助于女性OAB的表现并影响治疗结果。CS是一种诱发的脊髓超敏状态，也是公认的中枢放大痛觉的机制。在疼痛文献中，CS的存在通常是通过对重复的、短暂的诱发疼痛刺激反应的时间总和的非侵入性实验评估来索引的。建议将其作为本病的病理生理学基础 几种疾病通常被称为“CS综合征”，如纤维肌痛、肠易激综合征、偏头痛、特发性下腰痛、慢性疲劳综合征和间质性膀胱炎/膀胱痛综合征。尽管OAB的病因尚不清楚，但大量的动物和体外研究表明，神经元信号的改变与传入神经活性的增加(包括正常静止的c-纤维的激活也有关)。 在疼痛传递中)，并改变了兴奋性信号的中枢神经系统处理。实验证据表明，与OAB有关的盆腔器官串扰的机制似乎类似于CS的机制，如果不是完全相同的话。然而，评估这种变化的可靠方法仍然难以捉摸，因此，病理生理机制是否以及如何影响OAB患者的表型和影响治疗结果尚不清楚。目前，对于OAB的诊断、预后或治疗反应尚无客观指标。因此，关于疾病机制的科学研究成果与患者管理原则之间存在脱节。拟议的研究旨在通过利用研究慢性疼痛和功能障碍的研究人员常用的既定临床研究方法来解决这些重大的知识差距。我们假设，在一部分患者中，类似的中枢敏化有助于OAB的表型，OAB中中枢敏化的存在可以通过诱发疼痛刺激的时间总和来索引，并且这一机制的存在可能会对OAB的治疗结果产生影响。在目标1中，雷诺兹博士将比较患有OAB和不患有OAB的女性的时间总和程度。在目标2中，使用症状和临床数据的聚类分析，雷诺兹博士将确定经验定义的女性亚群，并将这些亚群的表型与时间总和的结果联系起来。最后，在目标3中，将在观察性队列研究中评估增加的时间总和和亚组表型对短期治疗结果的可预测性。

 DESCRIPTION (provided by applicant): The overarching goal of this career development award is to provide a comprehensive training program to prepare Dr. Reynolds for an independently funded clinical research career focused on outcomes of treatments for patients with overactive bladder (OAB). Dr. Reynolds is an Assistant Professor of Urologic Surgery and board-certified urologist with clinical subspecialty fellowship training in Female Pelvic Medicine and Reconstructive Surgery (FPMRS) and an advanced degree in health services and outcomes research (Masters of Public Health, MPH). Dr. Reynolds' near-term goal is to acquire additional expertise in clinical and translational research techniques while continuing a productive line of investigation into the clinical manifestations and treatment effects of underlying afferent nerve or visceral hyperactivity (a proposed mechanism for OAB). This award will allow him to meet this goal with formal graduate-level coursework and protection for 5 years of mentored research. Dr. Reynolds has assembled a multidisciplinary mentoring team to help accomplish this goal. His primary mentor is Stephen Bruehl, PhD, who has a well-established track record of high impact clinical and translational research in mechanisms of chronic pain and visceral hypersensitivity. His career development is further benefited by two co-mentors: David Penson, MD, MPH, is a urologist and experienced investigator with expertise in comparative effectiveness and outcomes research in quality of life and survivorship of prostate cancer; and Roger Dmochowski, MD, MMHC, is a urologist and an internationally recognized expert in overactive bladder and functional bladder disorders. Vanderbilt University Medical Center provides a rich environment for research and the training of young investigators with centralized oversight of all mentored physician scientists through the Office of Clinical & Translational Scientist Development, including the Vanderbilt Physician Scientist Development program that provides funding for Dr. Reynolds' protected time for research and career development activities. Furthermore, as a member of the Vanderbilt Center for Health Services Research and the Center for Surgical Quality and Outcomes Research, Dr. Reynolds has immediate access to investigators, invited speakers, and state-of-the-art core research facilities. His long-term goal s to become an independently-funded surgeon-scientist with the unique skills and training to bridge translational, clinical and health services studies within a large translational OAB research program that will impact the care of patients with this disease. The strong mentorship, additional training, and environment detailed in this proposal will position him to ultimately reac this objective. The research proposal will examine how spinally-mediated afferent hyperactivity, specifically central sensitization (CS), contributes to manifestations of OAB in women and affects treatment outcomes. CS is an induced state of spinal hypersensitivity and a well-recognized mechanism of centrally amplified pain perception. The presence of CS is routinely indexed in the pain literature by noninvasive experimental assessment of temporal summation in response to repetitive, brief evoked pain stimuli. It is proposed to underlie pathophysiology of several disorders often referred to as "CS syndromes," such as fibromyalgia, irritable bowel syndrome, migraine, idiopathic low back pain, chronic fatigue syndrome, and interstitial cystitis/bladder pain syndrome. Although the etiology of OAB remains unclear, a substantive body of animal and ex vivo research implicates altered neuronal signaling with both increased afferent nerve activity (including activation of normally quiescent c-fibers that are also involved in pain transmission) and altered CNS processing of excitatory signals. Experimental evidence suggests mechanisms of pelvic organ cross-talk which have been implicated in OAB appear analogous, if not identical, to mechanisms of CS. However, a reliable means to assess such changes has remained elusive, and therefore whether and how pathophysiologic mechanisms might contribute to OAB patient phenotypes and influence treatment outcomes is unknown. There is presently no objective marker for OAB diagnosis, prognosis or treatment response. As a result, there is a disconnect between scientific research findings on disease mechanisms and principles of patient management. The proposed research aims to address these significant knowledge gaps by leveraging established clinical research methods commonly used by investigators studying chronic pain and functional disorders. We hypothesize that similar central sensitization contributes to OAB phenotype in a subset of patients, that presence of central sensitization in OAB can be indexed by temporal summation of evoked pain stimuli, and that presence of this mechanism may have implications for OAB treatment outcomes. In Aim 1, Dr. Reynolds will compare the degree of temporal summation between women with and without OAB. In Aim 2, using cluster analysis on symptoms and clinical data, Dr. Reynolds will identify empirically defined subgroups of women and associate phenotypes of those subgroups with results of temporal summation. Finally, in Aim 3, the predictability of increased temporal summation and subgroup phenotypes on short-term treatment outcomes will be assessed in an observational cohort study.