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

基本信息

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
项目类别：
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

项目摘要

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.

该项目的目标是表征脊髓损伤引起的下尿路 (LUT) 功能障碍并测试新疗法。脊髓损伤的影响是多方面的，涉及脊髓、周围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、间质细胞起搏器活性、传入神经敏化和平滑肌细胞肥大。待测试的疗法包括A血清型肉毒杆菌神经毒素、|33-肾上腺素能受体激动剂、PDE-5抑制剂以及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对于研究 LUT 非常有效，并且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剂，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、神经元、间质和平滑肌细胞。 GCaMP4编码的病毒载体将用于标记支配膀胱的感觉神经以及控制膀胱和尿道括约肌的脊髓中的感觉神经和运动神经元。该项目的 Pis 和核心主任在泌尿科研究和光学测绘方面拥有丰富的专业知识。项目 1 和成像核心联合主任 Anthony Kanai 是传入神经、尿路上皮和间质细胞相互作用方面的专家，并且是第一个使用光学映射来研究 LUT 的人。项目 2 的 Lori Birder 是尿路上皮细胞病理生理学专家，也是第一个证明其神经元样特性的人。项目 3 的 Naoki Yoshimura 是感觉神经元病理生理学专家，第一个证明 DRG 神经元中离子通道表达的变化是膀胱传入敏化的机制。 William de Groat，项目 4 和动物核心主任，是 LUT 自主病理生理学专家，也是第一个展示 C 纤维传入在膀胱过度活动中的作用的人。 Guy Salama 是成像核心联合主任，是光学测绘领域的专家，也是第一个开发出同时记录动作电位和 Ca2+ 瞬变的方法的人。我们相信，我们的经验和独特的方法将带来一个非常互动和富有成效的计划。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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