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: 9766273
• 负责人: William Stuart Reynolds
• 金额: $ 14.8万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766273
• 关键词: Academic Medical Centers; Address; Affect; Age; Animals; Award; Bladder Diseases; C Fiber; 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; Fibromyalgia; Frequencies; Functional disorder; Funding; Goals; Health Services; Health Services Research; Hyperactive behavior; Hypersensitivity; Individual; International; 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; Painless; Patient Care; Patients; Pelvis; Phenotype; Physicians; Positioning Attribute; Prediction of Response to Therapy; 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; chronic painful condition; clinical phenotype; comparative effectiveness; cost effective; effectiveness research; experience; indexing; member; micturition urgency; multidisciplinary; neurotransmission; outcome forecast; pain perception; patient subsets; personalized medicine; professor; prognostic assays; prognostic value; programs; public health relevance; research and development; research facility; response; skills; skills training; societal costs; survivorship; translational scientist; 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全面的培训计划，帮助 Reynolds 博士为独立资助的临床研究职业做好准备，重点关注膀胱过度活动症 (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，接受过女性盆腔医学和重建外科 (FPMRS) 临床专科进修培训，并拥有卫生服务和结果研究高级学位（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更多专业知识，同时继续对潜在传入神经或内脏过度活跃（OAB 的拟议机制）的临床表现和治疗效果进行富有成效的研究。该奖项将使他能够通过正式的研究生水平课程并保护 5 年的指导研究来实现这一目标。雷诺兹博士组建了一支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方面拥有高影响力的临床和转化研究的良好记录。他的职业发展进一步得益于两位共同导师：David Penson，医学博士、公共卫生硕士，是一位泌尿科医生和经验丰富的调查员，在前列腺癌生活质量和生存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，是一位泌尿科医生，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为年轻研究人员的研究和培训提供了丰富的环境，并通过临床和转化科学家发展办公室对所有受指导的医师科学家进行集中监督，其中包括范德比尔特医师科学家发展计划，该计划为雷诺兹博士受保护的研究和职业发展活动时间提供资金。此外，作为范德比尔特健康服务研究中心和手术质量和结果研究中心的成员，雷诺兹博士可以立即接触研究人员、受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，能够在大型转化 OAB 研究项目中架起转化、临床和健康服务研究的桥梁，该项目将影响这种疾病患者的护理。本提案中详细介绍的强有力的指导、额外的培训和环境将使他最终实现这一目标。该研究计划将研究脊髓介导的传入过度活跃，特别是中枢敏化 (CS)，如何导致女性 OAB 的表现并影响治疗结果。 CS 是一种诱发的脊柱过敏状态，也是一种公认​​的中枢放大疼痛感知机制。 CS 的存在通常通过响应重复、短暂诱发疼痛刺激的时间总和的无创实验评估来在疼痛文献中索引。建议作为病理生理学的基础 几种通常被称为“CS综合征”的疾病，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。尽管 OAB 的病因尚不清楚，但大量动物和离体研究表明，神经元信号传导发生改变，传入神经活动增加（包括通常静止的 c 纤维的激活，这些神经元信号也参与其中） 疼痛传递）并改变中枢神经系统对兴奋信号的处理。实验证据表明，与 OAB 相关的盆腔器官串扰机制似乎与 CS 机制相似（即使不相同）。然而，评估此类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 患者表型并影响治疗结果尚不清楚。目前尚无 OAB 诊断、预后或治疗反应的客观标志。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。我们假设相似的中枢敏化对一部分患者的 OAB 表型有贡献，OAB 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，并且这种机制的存在可能对 OAB 治疗结果产生影响。在目标 1 中，Reynolds 博士将比较患有和不患有 OAB 的女性之间的时间总和程度。在目标 2 中，雷诺兹博士将使用对症状和临床数据的聚类分析来识别凭经验定义的女性亚组，并将这些亚组的表型与时间求和的结果相关联。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。

项目成果

Perioperative complications of conduit urinary diversion with concomitant cystectomy for benign indications: A population-based analysis.

良性适应症导管尿流改道联合膀胱切除术的围手术期并发症：基于人群的分析。

• DOI: 10.1002/nau.23135
• 发表时间: 2017
• 期刊: Neurourology and urodynamics
• 影响因子: 2
• 作者: Brown,ElizabethTimbrook;Osborn,David;Mock,Stephen;Ni,Shenghua;Graves,AmyJ;Milam,Laurel;Milam,Douglas;Kaufman,MelissaR;Dmochowski,RogerR;Reynolds,WStuart
• 通讯作者: Reynolds,WStuart

Temporal Trends in Conduit Urinary Diversion With Concomitant Cystectomy for Benign Indications: A Population-based Analysis.

良性适应症导管尿流改道联合膀胱切除术的时间趋势：基于人群的分析。

• DOI: 10.1016/j.urology.2016.06.035
• 发表时间: 2016
• 期刊: Urology
• 影响因子: 2.1
• 作者: Brown,ElizabethTimbrook;Osborn,David;Mock,Stephen;Ni,Shenghua;Graves,AmyJ;Milam,Laurel;Milam,Douglas;Kaufman,MelissaR;Dmochowski,RogerR;Reynolds,WStuart
• 通讯作者: Reynolds,WStuart

Somatic syndromes and chronic pain in women with overactive bladder.

• DOI: 10.1002/nau.23060
• 发表时间: 2017-04
• 期刊: NEUROUROLOGY AND URODYNAMICS
• 影响因子: 2
• 作者: Reynolds, W. Stuart;Mock, Stephen;Zhang, Xuechao;Kaufman, Melissa;Wein, Alan;Bruehl, Stephen;Dmochowski, Roger
• 通讯作者: Dmochowski, Roger

Does central sensitization help explain idiopathic overactive bladder?

• DOI: 10.1038/nrurol.2016.95
• 发表时间: 2016-08
• 期刊: Nature reviews. Urology
• 作者: Reynolds WS;Dmochowski R;Wein A;Bruehl S
• 通讯作者: Bruehl S

Underactive bladder in women: is there any evidence?

女性膀胱功能低下：有证据吗？

• DOI: 10.1097/mou.0000000000000280
• 发表时间: 2016
• 期刊: Current opinion in urology
• 影响因子: 2.5
• 作者: Cohn,JoshuaA;Brown,ElizabethT;Kaufman,MelissaR;Dmochowski,RogerR;Reynolds,WStuart
• 通讯作者: Reynolds,WStuart