ROLE OF NITRIC OXIDE IN INTERSTITIAL CYSTITIS

描述（改编自申请人的摘要）：最近的证据表明 膀胱传入细胞或上皮细胞的改变可以 导致神经兴奋性的变化，可能是病因的一部分 间质性膀胱炎（IC）。 IC是一种原因不明的慢性临床综合征 并呈现出不同且复杂的感觉症状。这可能涉及一个 传入神经元的主要缺陷或其周围环境的变化。 初步数据表明猫体内的 IC 可以改变化学物质的释放 来自传入神经以及神经的介质（一氧化氮、NO、ATP） 尿路上皮。有人建议改变化学物质的释放可能会影响 通过增加传入兴奋性以及尿路上皮膜功能 对有毒物质的渗透性。这些数据提出了这样的可能性： 尿路上皮参与膀胱的细胞间信号传导 神经-上皮相互作用可以调节膀胱功能。拟议的 实验将使用新方法，例如培养尿路上皮细胞和 自然发生的动物模型中的选择性NO卟啉微传感器 IC（猫间质性膀胱炎），已被证明与许多 与人类 IC 的相似性，以检验化学和/或 传入细胞或上皮细胞的细胞内信号传导机制 IC 中膀胱发生改变。自然发生的 IC，而非急性 健康动物的膀胱损伤或炎症模型允许更相关 IC病理生理学研究。目标 #1 将评估以下特征 正常猫和 IC 猫的尿路上皮。接下来传入神经的位置 对尿路上皮的影响表明尿路上皮细胞可能是 膀胱神经释放的递质或上皮细胞释放的递质 可以改变传入神经的兴奋性。目标 #2 将评估 正常猫和 IC 猫的膀胱传入特征。我们会 评估正常膀胱传入的特性以确定传入的方式 可以在IC中更改。这些研究可能导致选择性药理学 旨在针对神经上皮释放或信号传导缺陷的干预措施 为病理生理学和临床研究提供新的前景 膀胱疾病的管理。

DESCRIPTION (Adapted from the Applicant's Abstract): Recent evidence suggests that alterations in afferents or epithelial cells in the urinary bladder can lead to changes in neural excitability and may be part of the etiology of interstitial cystitis (IC). IC is a chronic clinical syndrome of unknown cause and presents with varying and complex sensory symptoms. This may involve a primary defect in afferent neurons or a change in their peripheral environment. Preliminary data indicate that IC in cats can alter the release of chemical mediators (nitric oxide, NO; ATP) from afferent nerves as well as the urothelium. It has been suggested that altered chemical release may influence afferent excitability as well as urothelial membrane function, by increasing the permeability to noxious substances. These data raise the possibility that the urothelium is involved in intercellular signaling in the urinary bladder and neural-epithelial interactions can modulate bladder function. The proposed experiments will use new methods such as cultured urothelial cells and a selective NO porphyrinic microsensor in a naturally occurring animal model of IC (feline interstitial cystitis), which has been demonstrated to have many similarities with IC in humans, to examine the hypothesis that chemical and/or intracellular signaling mechanisms in afferent or epithelial cells in the urinary bladder are altered in IC. Naturally occurring IC rather than acute bladder injury or inflammation models in healthy animals permit more relevant studies of pathophysiology of IC. Aim #1 will evaluation the characteristics of the urothelium in both normal and IC cats. The location of afferent nerves next to the urothelium suggests that urothelial cells might be targets for transmitters released from bladder nerves or that release by epithelial cells could alter the excitability of afferents. Aim #2 will evaluate the characteristics of bladder afferents in both normal and IC cats. We will evaluate the properties of normal bladder afferents to determine how afferents can be altered in IC. These studies may lead to selective pharmacologic interventions aimed at targeting neural-epithelial release or signaling defects and could provide a new prospective on the pathophysiology and clinical management of bladder disorders.