Afferent Hyperactivity Mechanisms in Overactive Bladder Syndrome

膀胱过度活动症候群的传入过度活跃机制

• 批准号: 9034073
• 负责人: William Stuart Reynolds
• 金额: $ 10.64万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034073
• 关键词: Academic Medical Centers; Accounting; Address; Affect; Age; Animals; Award; Bladder Diseases; CNS processing; Caring; Characteristics; Chronic Fatigue Syndrome; Clinical; Clinical Data; Clinical Management; Clinical Research; Clinical Services; Cluster Analysis; Cohort Studies; Comorbidity; Development; Diagnosis; Disease; Doctor of Philosophy; Environment; Etiology; Fellowship; Female; Fiber; Fibromyalgia; Frequencies; Functional disorder; Funding; Goals; Health Services; Health Services Research; Hyperactive behavior; Hypersensitivity; Individual; Interstitial Cystitis; Investigation; Irritable Bowel Syndrome; K-Series Research Career Programs; Knowledge; Literature; Low Back Pain; Malignant neoplasm of prostate; Master of Public Health; Measures; Mediating; Medicine; Mentors; Mentorship; Methods; Migraine; National Institute of Diabetes and Digestive and Kidney Diseases; Neuraxis; Nocturia; Observational Study; Operative Surgical Procedures; Organ; Outcome; Outcomes Research; Outcomes and Health Services Research; Overactive Bladder; Pain; Pain Disorder; Painless; Patient Care; Patients; Pelvis; Perception; Phenotype; Physicians; Positioning Attribute; Program Development; Proliferating; Public Health; Quality of life; Reconstructive Surgical Procedures; Reporting; Research; Research Methodology; Research Personnel; Research Proposals; Research Technics; Research Training; Scientist; Sensory; Severities; Signal Transduction; Spinal; Stimulus; Subgroup; Surgeon; Symptoms; Syndrome; Testing; Therapeutic; Time; Training; Training Programs; Translational Research; Treatment Failure; Treatment outcome; United States; Urinary Incontinence; Urologic Diseases; Urologic Surgical Procedures; Urologist; Visceral; Woman; afferent nerve; base; career; career development; central sensitization; chronic pain; comparative effectiveness; cost; cost effective; experience; indexing; meetings; member; micturition urgency; multidisciplinary; neurotransmission; outcome forecast; personalized medicine; professor; prognostic; programs; public health relevance; research and development; research facility; response; skills; skills training; survivorship; transmission process; treatment effect; treatment response; urinary

 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.

 描述（由申请人提供）：该职业发展奖的总体目标是提供一个全面的培训计划，为Reynolds博士独立资助的临床研究职业生涯做好准备，该职业生涯专注于膀胱过度活动症（OAB）患者的治疗结果。Reynolds博士是泌尿外科助理教授和委员会认证的泌尿科医生，拥有女性盆腔医学和重建外科（FPMRS）的临床亚专业奖学金培训以及卫生服务和成果研究的高级学位（公共卫生硕士，MPH）。Reynolds博士的近期目标是获得临床和转化研究技术方面的额外专业知识，同时继续对潜在传入神经或内脏活动过度（OAB的拟议机制）的临床表现和治疗效果进行富有成效的调查。该奖项将使他能够通过正式的研究生课程和5年的指导研究保护来实现这一目标。Reynolds博士组建了一个多学科的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高敏感性机制的高影响力临床和转化研究方面有着良好的记录。他的职业发展进一步受益于两位共同导师：大卫彭森，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者，在前列腺癌的生活质量和生存率方面具有比较有效性和结果研究的专业知识;罗杰·德莫霍夫斯基，医学博士，MMHC，是一名泌尿科医生，也是国际公认的膀胱过度活动症和功能性膀胱疾病专家。范德比尔特大学医学中心提供了一个丰富的研究和年轻研究人员的培训环境，通过临床和转化科学家发展办公室，包括范德比尔特医生科学家发展计划，为Reynolds博士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，Reynolds博士可以立即接触研究人员、特邀演讲者和最先进的核心研究设施。他的长期目标是成为一名独立资助的外科医生科学家，拥有独特的技能和培训，在一个大型转化OAB研究计划中连接转化，临床和卫生服务研究，这将影响这种疾病患者的护理。强有力的指导，额外的培训，以及本建议书中详细介绍的环境将使他最终实现这一目标。该研究计划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是脊髓超敏反应的诱导状态，是公认的中枢放大疼痛感知机制。在疼痛文献中，CS的存在通常通过对重复的短暂诱发疼痛刺激进行时间总和的无创性实验评估来索引。它被认为是 通常称为“CS综合征”的几种疾病，例如纤维肌痛、肠易激综合征、偏头痛、特发性腰痛、慢性疲劳综合征和间质性膀胱炎/膀胱疼痛综合征。虽然OAB的病因尚不清楚，但大量的动物和离体研究表明，神经元信号传导的改变与传入神经活动的增加（包括正常静止的c纤维的激活， 在疼痛传递中）和兴奋性信号的CNS处理改变。实验证据表明，与OAB有关的盆腔器官串扰机制与CS机制相似（如果不相同）。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可能有助于OAB患者表型和影响治疗结果尚不清楚。目前还没有OAB诊断、预后或治疗反应的客观标志物。因此，关于疾病机制的科学研究结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性疾病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，类似的中枢致敏有助于OAB表型在一个子集的患者，中枢致敏OAB中的存在可以通过诱发疼痛刺激的时间总和来索引，这种机制的存在可能对OAB治疗结果有影响。在目标1中，Reynolds博士将比较有和没有OAB的女性之间的时间总和程度。在目标2中，使用症状和临床数据的聚类分析，Reynolds博士将确定经验定义的女性亚组，并将这些亚组的表型与时间总和的结果相关联。最后，在目标3中，将在一项观察性队列研究中评估时间总和和亚组表型增加对短期治疗结局的可预测性。