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: 8526451
• 负责人: LORI A BIRDER
• 金额: $ 35.04万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526451
• 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; 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（由申请人提供）：膀胱疼痛综合征/间质性膀胱炎（PBS/IC）是一种慢性膀胱疼痛性疾病，目前尚无已证实的病因，也没有有效的治疗方法能够改善包括尿频在内的症状、尿急、夜尿和疼痛。家猫有一种类似的疾病，称为猫间质性膀胱炎 (FIC)，它表现出人类 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/炎症不同，患有这种自然发生疾病的猫可能允许对人类 PBS/IC 的病理生理学进行更多相关研究。我们已经发现 FIC 膀胱尿路上皮的许多异常，包括屏障功能、增殖和生长的改变，以及对化学和物理刺激的敏感性/反应增强。这些可能是细胞内 Ca2+ 释放/封存和/或细胞内信号传导途径变化的结果。 FIC 膀胱传入神经也存在异常，包括形态/电特性、神经放电和神经纤维分布的改变。此外，我们还有证据表明盆腔传入输入区域 FIC 脊髓胶质细胞形态和功能的长期改变表明这些细胞在异常感觉机制的产生中发挥作用。这些 FIC 细胞类型在长期培养过程中发生的持续变化给了我们不同的视角，表明沿着感觉通路发生多种变化的可能性。最近的研究结果支持脊髓神经胶质细胞的激活在持续性疼痛的引发和放大中发挥重要作用，因为众所周知，这些细胞可以增强和延长二级脊髓感觉神经元对周围刺激的反应。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，或者尿路上皮中的原发性缺陷可能依次触发更近端部位的继发性缺陷。我们在此更新应用中的目标是进一步了解尿路上皮（和神经胶质细胞）功能中观察到的持续变化背后的信号传导途径，以及负责各种细胞间相互作用的信号传导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方法来实现，包括成像技术、分子生物学和发射器释放测量。目标#1 将评估调节 PBS/FIC 中尿路上皮囊泡回收和递质释放的细胞内机制。我们假设尿路上皮响应机械或化学刺激而释放介质/信号因子导致了诊断为 FIC 的猫的感觉症状。该目标将利用膜非渗透性染料成像来探索尿路上皮细胞化学和机械诱发介质释放的机制。目标 #2 将评估 PBS/FIC 中伞状细胞形态、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尿路上皮培养物来测量顶端细胞特性和尿路上皮层之间的细胞信号传导的变化。目标 #3 将评估 PBS/FIC 中脊髓神经胶质细胞的形态/功能特性。我们将描述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 中神经胶质-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 PBS/IC 临床管理新靶点的开发提供重要的见解。 公众健康相关性：膀胱疼痛综合征/间质性膀胱炎 (PBS/IC) 是一种慢性、特发性膀胱疼痛性疾病，通常被描述为尿路上皮（膀胱腔内衬的上皮层）疾病。猫的一种类似疾病称为猫间质性膀胱炎 (FIC)，几乎表现出人类 PBS/IC 的所有特征和症状。这是一项拨款的更新申请，我们确定 FIC-尿路上皮对化学和物理刺激表现出高度的敏感性，随后尿路上皮衍生的递质释放增加。这些研究将检查这种类型的非神经元异常性疼痛/痛觉过敏的机制。了解促成和维持这些类型变化的机制可能为确定未来膀胱疾病（如 PBS/IC）临床管理的新靶点提供重要见解。