Role of Nitric Oxide in Interstitial Cystitis

一氧化氮在间质性膀胱炎中的作用

• 批准号: 7467993
• 负责人: LORI A BIRDER
• 金额: $ 30.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467993
• 关键词: Acids; Afferent Neurons; Animal Model; Autocrine Communication; Bladder; Bladder Urothelial Cell; Bladder Urothelium; Calcium; Capsaicin; Cell Communication; Cells; Chemicals; Clinical Management; Communication; Complex; Coupling; Data; Defect; Disease; Disruption; Electrophysiology (science); Etiology; Exhibits; Family Felidae; Felis catus; Fire - disasters; Funding; Future; Gated Ion Channel; Generations; Goals; Human; Human Characteristics; Image; Imaging Techniques; In Vitro; Increased frequency of micturition; Interstitial Cystitis; Ion Channel; Lead; Ligands; Link; Measurement; Mechanics; Mediator of activation protein; Methodology; Methods; Modification; Molecular; Molecular Biology; Nerve; Neurons; Nitric Oxide; Nociception; Nocturia; Numbers; Pain; Pain Disorder; Pathway interactions; Permeability; Physical environment; Platelet Factor 4; Primary Cell Cultures; Process; Property; Protein Kinase; Receptor Activation; Research Personnel; Role; Second Messenger Systems; Sensory; Signal Pathway; Signal Transduction; Spinal Ganglia; Stimulus; Symptoms; Syndrome; TRPV1 gene; Technology; Thinking; Transducers; Urothelial Cell; Urothelium; Work; afferent nerve; base; cell type; cellular imaging; chemical function; chemical release; chronic pain; immunocytochemistry; insight; intercellular communication; interdisciplinary approach; loris; novel; patch clamp; programs; receptor; receptor sensitivity; response; second messenger; sensor; voltage

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.

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，其中没有经过证实的病因，也没有能够根除症状的有效治疗方法，这些症状包括尿频，尿急，排尿困难和疼痛。在猫中有一种类似的疾病，称为猫间质性膀胱炎（FIC），它表现出几乎所有的人类IC的特征，包括大多数（如果不是全部）症状。我们已经确定了一些异常的尿路（屏障功能的改变，增加对化学和机械刺激的反应），以及传入神经（增加对化学和机械刺激，包括不同的放电特性的反应）在FIC。其他发现支持了一个一般假设，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。使用多学科的方法，包括分子生物学，测量发射器释放，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传入和尿路上皮功能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改变尿路上皮细胞中“传感器”和“换能器”功能的机制。前提是自分泌信号传导/细胞内Ca 2+（释放/螯合）的常见缺陷可能是FIC症状的关键因素。这种变化可能是尿道刺激的“传感器”（即对热、机械和化学刺激作出反应的能力）以及“转换器”（即释放化学物质的能力）功能改变的基础。目的#2将评价尿路上皮细胞和/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中两种细胞类型中是否发生类似的通道反应性变化。目标#3将评估FIC对细胞-细胞相互作用的影响。我们将研究FIC如何影响尿路上皮细胞的增殖/分化以及尿路上皮细胞通讯的机制。了解有助于和维持这些类型的变化的机制，可能会提供重要的见解，为识别新的目标，为未来的临床管理IC。