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.

该计划的目标是表征由于脊髓损伤并测试新疗法，较低的尿路（LUT）功能障碍。脊髓损伤的作用是多方面的，涉及脊髓，周围神经元的变化以及膀胱和尿道的不同细胞类型，导致衰弱 - 肾上腺素障碍，尿路上皮细胞增生，间天质性细胞动物起搏器活性，亲切的神经敏感性和平滑肌肉细胞性细胞超生体。要测试的疗法包括肉毒神经毒素血清型A，| 33-肾上腺素能受体激动剂，PDE-5抑制剂，神经生长因子以及脑源性的神经营养因子抗体。我们开发的光学映射技术在研究LUT方面非常有效，并且是项目之间的关键联系。这些方法利用独特的小鼠和大鼠制剂，包括脊髓切片，膀胱尿布片，带有脊柱神经的床单，壁横截面以及“内联”原发性尿路上皮，神经元，间质和平滑肌细胞。 GCAMP4编码的病毒载体将用于标记感官神经，该感官神经支配膀胱神经，感觉神经和运动神经元在控制膀胱和尿道括约肌的脊髓中。 PIS和核心主管在泌尿科研究和光学映射方面具有广泛的专业知识。 Anthony Kanai是项目1和Imaging Core共同导演，是传入神经，尿路上皮和间质细胞相互作用的专家，并首先使用光学映射来研究LUT。项目2洛里·伯德（Lori Birder）是尿路上皮细胞病理生理学的专家，并首先证明了其神经元样性能。项目3项目Naoki Yoshimura是感觉神经元病理生理学的专家，首先证明DRG神经元中离子通道表达的变化是膀胱传入敏化的机制。项目4项目和动物核心主管William de Groat是LUT的自主病理生理学专家，并首先展示了C纤维传入在膀胱过度活动中的作用。成像核心联合导演的盖伊·萨拉马（Guy Salama）是光学映射的专家，并且首先开发了同时记录动作电位和CA2+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果的计划。

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