SUPRASPINAL TARGETS IN NEUROGENIC VOIDING DYSFUNCTION

项目总结/摘要 博士Khavari是多学科K12泌尿学研究职业发展计划的最后一年 (Lamb：董事; Boone：联合董事），正在申请个人职业发展奖 (K23)支持她转变为神经泌尿学和排尿领域完全独立的外科医生-科学家 功能障碍K23奖将专门为Khavari博士提供在两个领域发展专业知识所需的支持： (1)高级功能磁共振成像（fMRI）协议设计和数据分析;（2）应用 经颅旋转永磁刺激器（TRPMS）的临床试验。为了实现目标，博士。 Khavari组建了一个由神经成像领域的合作者和顾问组成的多学科专家团队 （Karmonik），神经科学（Masdeu和Helekar），神经泌尿学（Chai和Daneshgari）和泌尿学研究 （Boone and Lamb）布恩博士，她的系主任，是神经泌尿学研究的领先专家， 曾指导许多初级教师独立调查，并将担任她的主要导师。 神经源性排尿功能障碍（VD）是病态的、昂贵的，并且导致尿路感染、结石、败血症和泌尿系统疾病。 永久性肾衰竭目前，唯一可用的VD治疗方法是导管插入术，这是一个负担， 特别是在神经源性患者中，例如多发性硬化症（MS），其通常表现出下肢 痉挛和手部灵活性受损费用和病态副作用（血尿、疼痛、创伤、狭窄， 和感染）与导管插入术，敦促我们寻找潜在的治疗选择以外的 膀胱，如脊髓上的目标。然而，目前对脊髓上中心的理解， 在神经源性VD患者中起启动或调节排尿的作用。卡瓦里医生会 使用她建立的功能磁共振成像和尿动力学同步平台的初步数据和原始数据库 目的1：预先选择的灰质区域的激活模式， 有VD的MS患者与无VD的MS患者的兴趣（ROI）不同，特别是有逼尿肌的患者 括约肌运动障碍目的2：损伤预先选择的参与膀胱控制的白色物质束， VD的独立预测指标。目的3：VD MS患者ROI中的靶向皮质刺激 引起ROI的变化，更好地概括了无VD患者或健康对照的激活模式。 目标3将是在选定的MS患者中使用针对个性化ROI的个性化TRPMS的试点试验 关于VD Khavari博士正在进行的研究和目前的职业发展计划表明了她对以下方面的承诺： 成为一个独立的研究者在以病人为导向的研究。她的项目有可能改善我们的 了解大脑控制膀胱的能力，提出新的诊断方法，并提供关键步骤， 神经源性（如MS或 中风）或非神经源性VD（例如膀胱活动不足或Fowler综合征）。这一建议，以及 随后计划的R 01，将为未来的VD治疗临床试验奠定基础。

Project Summary/Abstract Dr. Khavari is in her final year of the Multidisciplinary K12 Urologic Research Career Development Program (Lamb: Director; Boone: Co-Director) from NIDDK and is applying for the Individual Career Development Award (K23) to support her transition into a fully independent surgeon-scientist in the fields of neurourology and voiding dysfunction. K23 award will specifically provide Dr. Khavari the support needed to develop expertise in 2 areas: (1) Advanced functional Magnetic Resonance Imaging (fMRI) protocol design and data analysis; (2) Application of Transcranial Rotating Permanent Magnet Stimulator (TRPMS) in a clinical trial. To achieve her goals, Dr. Khavari has assembled an expert multidisciplinary team of collaborators and advisors in neuroimaging (Karmonik), neuroscience (Masdeu and Helekar), neurourology (Chai and Daneshgari), and urologic research (Boone and Lamb). Dr. Boone, the chair of her Department, is a leading expert in neuro-urological research and has mentored many junior faculty to independent investigators and will serve as her Primary Mentor. Neurogenic voiding dysfunction (VD) is morbid, costly, and leads to urinary tract infections, stones, sepsis, and permanent renal failure. Currently, the only available therapy for VD is catheterization, which is a burden, especially in neurogenic patients, such as Multiple Sclerosis (MS), who commonly exhibit lower extremity spasms and compromised hand dexterity. The cost and morbid side effects (hematuria, pain, trauma, strictures, and infections) associated with catheterizations, urge us to look into potential therapeutic options beyond the bladder, such as supraspinal targets. Yet, the current understanding of supraspinal centers, and their roles in initiating or modulating voiding, is rudimentary in patients with neurogenic VD. Dr. Khavari will use preliminary data and the raw database from her established simultaneous fMRI and urodynamics platform to determine whether, in female MS subjects: Aim 1: Activation patterns of preselected grey matter Regions of Interest (ROI)s are different among MS patients with versus without VD, specifically those with Detrusor Sphincter Dyssenergia. Aim 2: Damage to preselected white matter tracts involved in bladder control provides an independent predictive measure for VD. Aim 3: Targeted cortical stimulation in ROIs in MS patients with VD causes changes in ROIs that better recapitulate the activation patterns in patients without VD or healthy controls. Aim 3 will be a pilot trial using an individualized TRPMS targeting personalized ROIs in selected MS patients with VD. Dr. Khavari’s ongoing research and current career development plans exemplify her commitment to becoming an independent investigator in patient-oriented research. Her project has the potential to improve our ability to understand brain control of bladder, suggest new diagnostic methods, and provide crucial steps towards therapeutic options for the morbid and intractable condition, VD, in patients with neurogenic (e.g. MS or Strokes) or non-neurogenic VD (e.g. underactive bladder or Fowler’s syndrome). This proposal, and the subsequent planed R01, will lay the foundation for future clinical trials addressing therapies for VD.