Role of Nitric Oxide in Interstitial Cystitis

描述（由申请人提供）：最近的证据表明传入神经和尿路上皮细胞都表现出许多共同的特性，包括某些受体和离子通道的表达。间质性膀胱炎（IC）是一种慢性膀胱疼痛疾病，目前尚无明确的病因，也没有有效的治疗方法能够根除尿频、尿急、夜尿和疼痛等症状。在猫身上也有一种类似的疾病，称为猫间质性膀胱炎（FIC），它表现出人类IC的几乎所有特征，包括大部分（如果不是全部）症状。我们已经发现在FIC中，尿路上皮（屏障功能改变，对化学和机械刺激的反应增加）和传入神经（对化学和机械刺激的反应增加，包括不同的放电特性）都存在一些异常。另外的研究结果支持了一个普遍的假设，即膀胱传入神经元和尿路上皮细胞的改变可能是FIC病因的一部分。使用多学科方法，包括分子生物学，测量递质释放，电生理学和成像技术使用光电二极管阵列，我们的目标是进一步了解在传入和尿路上皮功能中观察到的变化的信号通路，以及负责各种细胞-细胞相互作用的信号机制，以及这些机制如何在FIC中改变。目的1将评估FIC改变尿路上皮细胞“传感器”和“传感器”功能的机制。前提是自分泌信号/细胞内Ca2+（释放/隔离）的共同缺陷可能是FIC症状的关键因素。这些变化可能是尿路上皮“传感器”（即对热、机械和化学刺激作出反应的能力）和“传感器”（即释放化学物质的能力）功能改变的基础。目的2将评估尿路上皮细胞和/或感觉神经元是否在FIC中表现出类似的离子通道表达/功能改变。我们将使用膜片钳记录来评估在FIC的两种细胞类型中是否发生类似的通道响应性变化。目的3将评估FIC对细胞间相互作用的影响。我们将研究FIC如何影响尿路上皮的增殖/分化以及尿路上皮通讯的机制。了解促成和维持这些类型变化的机制可能为未来IC临床管理的新靶点的确定提供重要见解。

DESCRIPTION (provided by applicant): Recent evidence has revealed that both afferent nerves and urothelial cells exhibit a number of common properties including the expression of certain receptors and ion channels. Interstitial cystitis (IC) is a chronic painful condition of the urinary bladder in which there are no proven etiologies and no effective treatments that are able to eradicate the symptoms, which include urinary frequency, urgency, nocturia and pain. There is a comparable disease in cats, termed feline interstitial cystitis (FIC), which demonstrates nearly all of the characteristics of human IC including most if not all of the symptoms. We have identified a number of abnormalities in both the urothelium (alterations in barrier function, increased responsiveness to chemical and mechanical stimuli) as well as in afferent nerves (increased response to chemical and mechanical stimuli including different firing properties) in FIC. Additional findings support a general hypothesis that alterations in bladder afferent neurons as well as in urothelial cells may be part of the etiology of FIC. Using a multidisciplinary approach including molecular biology, measurement of transmitter release, electrophysiology and imaging techniques using photodiode arrays, our goals are to further understand the signaling pathways underlying the changes observed in both afferent and urothelial function, as well as signaling mechanisms responsible for various cell-cell interactions and how these mechanisms may be altered in FIC. Aim #1 will evaluate the mechanism by which FIC alters "sensor" and "transducer" functions in urothelial cells. The premise is that a common defect in autocrine signaling/ intracellular Ca2+ (release/sequestration) could be a key contributor to the symptoms of FIC. Such changes could underlie alterations in the "sensor" (i.e. ability to respond to thermal, mechanical and chemical stimuli) as well as "transducer" (i.e. ability to release chemicals) function of urothelium. Aim #2 will evaluate whether urothelial cells and/or sensory neurons exhibit similar alterations in ion channel expression/function in FIC. We will use patch clamp recording to evaluate whether similar changes in channel responsiveness occur in both cell types in FIC. Aim #3 will evaluate the effect of FIC on cell-cell interactions. We will examine how FIC can influence urothelial proliferation/differentiation as well as mechanisms of urothelial communication. Understanding the mechanisms contributing to and maintaining these types of changes may provide important insights for the identification of novel targets for the future clinical management of IC.