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

这个项目的目标是表征下尿路（LUT）功能障碍由于脊髓损伤和测试新的治疗方法。脊髓损伤的影响是多方面的，包括脊髓、外周神经元以及膀胱和尿道中不同类型细胞的改变，导致尿路上皮细胞增生、间质细胞起搏器活性、传入神经致敏和平滑肌细胞肥大。待测试的治疗方法包括A型肉毒杆菌神经毒素、bbb33 -肾上腺素能受体激动剂、PDE-5抑制剂、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剂，包括脊髓切片、膀胱尿道片、脊髓神经片、壁横截面和“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支配膀胱的感觉神经以及控制膀胱和尿道括约肌的脊髓感觉神经和运动神经元。项目pi和核心主任在泌尿学研究和光学制图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方面的专家，也是第一个使用光学制图来研究LUT的人。项目2的Lori Birder是尿路上皮细胞病理生理学方面的专家，她是第一个证明它们具有神经元样特性的人。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致敏的机制。项目4和动物核心主任William de Groat是LUT自主神经病理生理学的专家，他是第一个证明c纤维传入在膀胱过度活动中的作用的人。Guy Salama是成像核心的联合主任，他是光学制图专家，也是第一个开发同时记录动作电位和Ca2+瞬态的方法的人。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方案。

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.