Mechanisms/Treatments of Lower Urinary Tract Dysfunction After Spinal Cord Injury

脊髓损伤后下尿路功能障碍的机制/治疗

• 批准号: 9319726
• 负责人: Anthony John Kanai
• 金额: $ 157.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319726
• 关键词: Action Potentials; Adrenergic Agonists; Afferent Neurons; Animals; Antibodies; Ataxia; Bladder; Bontoxilysin; Brain-Derived Neurotrophic Factor; C Fiber; Cell Communication; Cells; Chemicals; Chest; Communication; Complement; Data; Defect; Disease; Dyes; Ensure; Event; Exhibits; Functional disorder; Goals; Hyperplasia; Hypertrophy; Image; Injectable; Injury; Instruction; Ion Channel; Label; Lead; Link; Lower urinary tract; Measurement; Methodology; Methods; Motor; Motor Neurons; Mus; Muscle Development; Nerve Growth Factors; Neural Pathways; Neurons; Optics; Overactive Bladder; Pathogenesis; Pathology; Patients; Peripheral; Permeability; Preparation; Property; Rattus; Reflex action; Regulation; Research; Role; Sensory; Serotyping; Slice; Smooth Muscle; Smooth Muscle Myocytes; Sphincter; Spinal; Spinal Cord; Spinal Ganglia; Spinal cord injury; Spinal nerve structure; Staining method; Stains; Techniques; Testing; Therapeutic Agents; Tissues; Urethra; Urethral sphincter; Urothelial Cell; Urothelial Hyperplasia; Viral Vector; afferent nerve; cell type; experience; inhibitor/antagonist; interstitial; interstitial cell; mad itch virus; muscle hypertrophy; nodal myocyte; novel therapeutic intervention; novel therapeutics; patch clamp; programs; public health relevance; relating to nervous system; success; synergism; urologic; voltage

The goals of this program are to characterize lower urinary tract (LUT) dysfunction due to spinal cord injury and to test new therapies. Effects of spinal cord injury are multifaceted involving changes in the spinal cord, peripheral neurons and different cell types in the bladder and urethra leading to detrusorsphincter- dyssynergia, urothelial cell hyperplasia, interstitial cell pacemaker activity, afferent nerve sensitization and smooth muscle cell hypertrophy. Therapies to be tested include botulinum neurotoxin serotype A, |33-adrenergic receptor agonists, PDE-5 inhibitrors, and nerve growth factor and brain-derived neurotrophic factor antibodies. Optical mapping techniques we developed are extremely effective in studying LUT and are a key link between projects. These approaches utilize unique mouse and rat preparations including spinal cord slices, bladder-urethra sheets, sheets with spinal nerves, wall cross-sections and 'inline' primary urothelial, neuronal, interstitial and smooth muscle cells. GCaMP4 encoded viral vectors will be used to label sensory nerves innervating the bladder and sensory nerves and motoneurons in the spinal cord controlling the bladder and urethral sphincter. The program Pis and core Directors have extensive expertise in urologic research and optical mapping. Anthony Kanai, project 1 and imaging core co-director, is an expert in afferent nerve, urothelial and interstitial cell interactions and was first to use optical mapping to study the LUT. Lori Birder, project 2, is an expert in urothelial cell pathophysiology and was first to demonstrate their neuronal-like properties. Naoki Yoshimura, project 3, is an expert in the pathophysiology of sensory neurons and was first to demonstrate changes in ion channel expression in DRG neurons as a mechanism for bladder afferent sensitization. William de Groat, project 4 and animal core director, is an expert on the autonomic pathophysiology of the LUT and was first to show the role of C-fiber afferents in bladder overactivity. Guy Salama, imaging core co-director, is an expert in optical mapping and was first to develop methods to simultaneously record action potentials and Ca2+ transients. We are confident that our experience and unique approaches will lead to a very interactive and fruitful program.

该项目的目标是描述脊髓损伤引起的下尿路（LUT）功能障碍，并测试新的治疗方法。脊髓损伤的影响是多方面的，涉及脊髓、外周神经元以及膀胱和尿道中不同细胞类型的变化，导致逼尿肌括约肌协同失调、尿路上皮细胞增生、间质细胞起搏活动、传入神经敏化和平滑肌细胞肥大。待测试的疗法包括肉毒杆菌神经毒素血清型A，|33-肾上腺素能受体激动剂、PDE-5受体激动剂、神经生长因子和脑源性神经营养因子抗体。我们开发的光学映射技术在研究LUT方面非常有效，是项目之间的关键环节。这些方法利用独特的小鼠和大鼠制备物，包括脊髓切片、膀胱尿道片、具有脊神经的片、壁横截面和“内联”原代尿路上皮细胞、神经元细胞、间质细胞和平滑肌细胞。GCaMP 4编码的病毒载体将用于标记支配膀胱的感觉神经和脊髓中控制膀胱和尿道括约肌的感觉神经和运动神经元。该计划PIS和核心主任在泌尿外科研究和光学映射方面拥有广泛的专业知识。Anthony Kanai，项目1和成像核心联合主任，是传入神经，尿路上皮和间质细胞相互作用的专家，并且是第一个使用光学映射来研究LUT的人。洛里伯德，项目2，是尿路上皮细胞病理生理学的专家，是第一个证明他们的神经元样属性。项目3的Naoki Yoshimura是感觉神经元病理生理学方面的专家，他首先证明了DRG神经元中离子通道表达的变化是膀胱传入敏化的一种机制。William de Groat，项目4和动物中心主任，是LUT自主神经病理生理学的专家，并且是第一个显示C纤维传入在膀胱过度活动中的作用的人。Guy Salama，成像核心联合主任，是光学映射的专家，是第一个开发同时记录动作电位和Ca 2+瞬变的方法。我们相信，我们的经验和独特的方法将导致一个非常互动和富有成效的计划。

项目成果

Role of p38 MAP kinase signaling pathways in storage and voiding dysfunction in mice with spinal cord injury.

• DOI: 10.1002/nau.24170
• 发表时间: 2020-01
• 期刊: Neurourology and urodynamics
• 影响因子: 2
• 作者: Shimizu N;Wada N;Shimizu T;Suzuki T;Kurobe M;Kanai AJ;de Groat WC;Hashimoto M;Hirayama A;Uemura H;Yoshimura N
• 通讯作者: Yoshimura N

Translating promising strategies for bowel and bladder management in spinal cord injury.

• DOI: 10.1016/j.expneurol.2018.05.006
• 发表时间: 2018-08
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Wheeler TL;Bowel and Bladder Workshop Participants;de Groat W;Eisner K;Emmanuel A;French J;Grill W;Kennelly MJ;Krassioukov A;Gallo Santacruz B;Biering-Sørensen F;Kleitman N
• 通讯作者: Kleitman N