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一些共同的特性，包括某些受体和离子通道的表达。间质性膀胱炎(IC)是一种慢性疼痛的膀胱状况，没有已证实的病因，也没有有效的治疗方法能够消除症状，包括尿频、尿急、夜尿和疼痛。在猫身上也有一种类似的疾病，称为猫科间质性膀胱炎(FIC)，它表现出几乎所有人类IC的特征，包括大多数症状。我们在FIC的尿路上皮细胞(屏障功能改变，对化学和机械刺激的反应性增加)和传入神经(对化学和机械刺激的反应增加，包括不同的激发特性)中都发现了一些异常。更多的发现支持一个普遍的假设，即膀胱传入神经元和尿路上皮细胞的改变可能是FIC的部分病因。我们的目标是利用包括分子生物学、递质释放测量、电生理学和光电二极管阵列成像技术在内的多学科方法，进一步了解在传入和尿路上皮功能观察到的变化背后的信号通路，以及负责各种细胞-细胞相互作用的信号机制，以及这些机制在FIC中可能发生的改变。目的1评价FIC改变尿路上皮细胞“感受器”和“转导”功能的机制。前提是自分泌信号/细胞内钙离子(释放/封存)的共同缺陷可能是FIC症状的关键因素。这些变化可能导致尿路上皮的“传感器”(即对热、机械和化学刺激的反应能力)以及“传感器”(即释放化学物质的能力)功能发生变化。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/功能的变化。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了类似的通道响应变化。目的#3将评估FIC对细胞-细胞相互作用的影响。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。了解导致和维持这些类型变化的机制可能会为识别未来IC临床治疗的新靶点提供重要的见解。

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.