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: 8321907
• 负责人: LORI A BIRDER
• 金额: $ 37.48万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321907
• 关键词: Acute; Afferent Neurons; Animal Model; Apical; Astrocytes; Bladder; Bladder Diseases; Brain; Cell Communication; Cell physiology; Cells; Cellular Morphology; Characteristics; Chemical Stimulation; Chemicals; Chemistry; Chronic; Clinical Management; Communication; Data; Defect; Development; Diagnosis; Disease; Distant; Dyes; Epithelial; Epithelium; Etiology; Exhibits; Family Felidae; Felis catus; Functional disorder; Funding; Future; Generations; Goals; Grant; Growth; Human; Hyperalgesia; Image; Imaging Techniques; Increased frequency of micturition; Inflammation; Injury; Interstitial Cystitis; Lead; Measurement; Measures; Mechanics; Mediator of activation protein; Membrane; Molecular Biology; Morphology; Nerve; Nerve Fibers; Neuroglia; Neurons; Nitric Oxide; Nocturia; Pain; Pathway interactions; Pelvis; Peripheral; Persistent pain; Physical Stimulation; Play; Probability; Process; Progress Reports; Property; Publishing; Recycling; Research; Rodent Model; Role; Sensory; Signal Pathway; Signal Transduction; Site; Spinal; Spinal Cord; Stimulus; Symptoms; Syndrome; Transducers; Urothelial Cell; Urothelium; Vesicle; allodynia; cell type; chronic pain; effective therapy; electrical property; in vivo; insight; interdisciplinary approach; novel; painful bladder syndrome; public health relevance; relating to nervous system; response; sensor; sensory mechanism

DESCRIPTION (provided by applicant): Painful bladder syndrome/Interstitial cystitis (PBS/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 ameliorate the symptoms, which include urinary frequency, urgency, nocturia and pain. There is a comparable disease in domestic cats termed feline interstitial cystitis (FIC), which demonstrates nearly all of the characteristics and symptoms of human PBS/IC. Cats with this naturally occurring disease, as opposed to acute injury/inflammation in rodent models, may permit more relevant studies of the pathophysiology of PBS/IC in humans. We have identified a number of abnormalities in the urothelium of FIC bladders including alterations in barrier function, proliferation and growth, and a heightened sensitivity/response to both chemical and physical stimuli. These may be a result of changes in intracellular Ca2+ release/sequestration and/or intracellular signaling pathways. There are also abnormalities in FIC bladder afferents including altered morphological/electrical properties, nerve firing and distribution of nerve fibers. Moreover, we also have evidence of long-term alterations in FIC spinal cord glial cell morphology and function in regions of pelvic afferent input suggesting that these cells play a role in the generation of abnormal sensory mechanisms. The persistent change that takes place in these FIC cell types during long-term culture has given us a different perspective suggesting the probability of multiple changes along the sensory pathway. Recent findings support an important role for activation of spinal cord glial cells in both initiation and amplification of persistent pain, as it is known that these cells can enhance and prolong the response of second order spinal sensory neurons to peripheral stimulation. Thus, multiple sites in the sensory pathway may have a similar type of 'primary' defect, or a primary defect in the urothelium may sequentially trigger a secondary defect at more proximal sites. Our goals in this renewal application are to further understand the signaling pathways underlying the persistent changes observed in urothelial (and glial cell) function, as well as signaling mechanisms responsible for various cell-cell interactions and how these mechanisms may be altered in FIC. These goals will be accomplished using a multidisciplinary approach including imaging techniques, molecular biology and measurement of transmitter release. Aim #1 will evaluate intracellular mechanisms regulating urothelial vesicle recycling and transmitter release in PBS/FIC. We hypothesize that the release of mediators/signaling factors from the urothelium in response to mechanical or chemical stimuli contributes to the sensory symptoms in cats diagnosed with FIC. This aim will utilize imaging with membrane-impermeant dyes in order to explore the mechanisms responsible for chemical and mechanical evoked release of mediators from urothelial cells. Aim #2 will evaluate mechanisms underlying changes in umbrella cell morphology, signaling and communication in PBS/FIC. We will use intact bladder sheets and polarized urothelial cultures to measure changes in apical cell properties and cell signaling between urothelial layers. Aim #3 will evaluate morphological/functional properties of spinal cord glial cells in PBS/FIC. We will characterize the chemistry/morphology and function of cultured spinal cord astrocytes as well as glial-neuronal interactions in normal and FIC. Understanding the mechanisms involved in these types of changes may provide important insights for the development of novel targets for the clinical management of PBS/IC. PUBLIC HEALTH RELEVANCE: Painful Bladder Syndrome/Interstitial Cystitis (PBS/IC) is a chronic, idiopathic painful condition of the urinary bladder which is often described as a disease of the urothelium (the epithelial layer lining the bladder lumen). A comparable disease in cats, termed feline interstitial cystitis (FIC), exhibits nearly all of the characteristics and symptoms to that of human PBS/IC. This is a renewal application of a grant where we determined that FIC-urothelium exhibits a heightened sensitivity to chemical and physical stimuli with subsequent augmentation of urothelial-derived transmitter release. These studies will examine mechanisms underlying this type of nonneuronal allodynia/hyperalgesia. Understanding the mechanisms contributing to and maintaining these types of changes may provide important insight for the identification of novel targets for the future clinical management of bladder diseases such as PBS/IC.

描述（由申请方提供）：膀胱疼痛综合征/间质性膀胱炎（PBS/IC）是一种慢性膀胱疼痛疾病，其病因尚未得到证实，也没有能够改善症状（包括尿频、尿急、排尿困难和疼痛）的有效治疗方法。在家猫中有一种类似的疾病，称为猫间质性膀胱炎（FIC），其表现出人类PBS/IC的几乎所有特征和症状。与啮齿动物模型中的急性损伤/炎症相反，患有这种自然发生疾病的猫可能允许对人体中PBS/IC的病理生理学进行更多相关研究。我们已经确定了一些异常的FIC膀胱的尿路上皮，包括屏障功能，增殖和生长的改变，并提高敏感性/化学和物理刺激的反应。这些可能是细胞内Ca 2+释放/螯合和/或细胞内信号传导途径变化的结果。在FIC膀胱传入中也存在异常，包括改变的形态/电特性、神经放电和神经纤维的分布。此外，我们也有证据表明，FIC脊髓胶质细胞形态和功能的长期改变，在盆腔传入输入的区域，这表明这些细胞在产生异常的感觉机制中发挥作用。在长期培养过程中，这些FIC细胞类型发生的持续变化给了我们一个不同的视角，表明感觉通路沿着多种变化的可能性。最近的研究结果支持脊髓胶质细胞的激活在持续性疼痛的起始和放大中的重要作用，因为已知这些细胞可以增强和延长二级脊髓感觉神经元对外周刺激的反应。因此，感觉通路中的多个部位可能具有类似类型的“原发性”缺陷，或者尿道鞘中的原发性缺陷可能在更近端的部位依次触发继发性缺陷。我们在此更新申请中的目标是进一步了解在尿路上皮（和神经胶质细胞）功能中观察到的持续变化的信号通路，以及负责各种细胞间相互作用的信号机制以及这些机制如何在FIC中改变。这些目标将使用多学科的方法来实现，包括成像技术，分子生物学和测量发射器释放。目的#1将评价在PBS/FIC中调节尿路上皮囊泡再循环和递质释放的细胞内机制。我们推测，释放介质/信号传导因子从尿路刺激响应机械或化学刺激有助于诊断为FIC的猫的感觉症状。这一目标将利用成像与膜不渗透染料，以探讨负责化学和机械诱发释放介质从尿路上皮细胞的机制。目的#2将评价PBS/FIC中伞细胞形态、信号传导和通讯变化的潜在机制。我们将使用完整的膀胱片和极化的尿路上皮培养来测量顶端细胞特性和尿路上皮层之间细胞信号的变化。目的#3将评价PBS/FIC中脊髓神经胶质细胞的形态/功能特性。我们将表征培养的脊髓星形胶质细胞的化学/形态和功能，以及正常和FIC中的胶质细胞-神经元相互作用。了解这些类型的变化所涉及的机制可能为开发用于PBS/IC临床管理的新靶点提供重要见解。 公共卫生相关性：膀胱疼痛综合征/间质性膀胱炎（PBS/IC）是膀胱的慢性、特发性疼痛病症，其通常被描述为尿道炎（膀胱腔内衬的上皮层）的疾病。猫的一种类似疾病，称为猫间质性膀胱炎（FIC），表现出几乎所有的特征和症状的人PBS/IC。这是一项资助的更新申请，我们确定FIC-尿路刺激对化学和物理刺激表现出更高的敏感性，随后增加尿路上皮衍生的递质释放。这些研究将探讨这种类型的非神经元异常性疼痛/痛觉过敏的机制。了解有助于和维持这些类型的变化的机制可能为识别未来膀胱疾病临床管理的新靶点（如PBS/IC）提供重要的见解。