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）：疼痛的膀胱综合征/间质性膀胱炎（PBS/IC）是泌尿膀胱的慢性疼痛疾病，在膀胱中没有可靠的病因，也没有能够改善症状的有效治疗方法，其中包括尿频率，紧急，静脉曲张和疼痛。在称为猫间质膀胱炎（FIC）的家猫中，有一种可比的疾病，该疾病几乎证明了人类PBS/IC的所有特征和症状。与啮齿动物模型中的急性损伤/炎症相反，患有这种天然疾病的猫可能允许对人类PBS/IC的病理生理学进行更相关的研究。我们已经确定了FIC膀胱尿皮细胞中的许多异常，包括屏障功能的改变，增殖和生长以及对化学和物理刺激的灵敏度/反应提高。这些可能是由于细胞内Ca2+释放/隔离和/或细胞内信号通路的变化的结果。 FIC膀胱传入中也存在异常，包括改变形态/电性能，神经释放和神经纤维的分布。此外，我们还有证据表明骨盆传入输入区域中FIC脊髓神经胶质细胞形态和功能的长期改变，这表明这些细胞在异常的感觉机制的产生中起作用。在长期培养过程中，在这些FIC细胞类型中发生的持续变化给了我们不同的观点，这表明沿感觉途径多次变化的可能性。最近的发现支持脊髓神经胶质细胞在持续疼痛的起始和扩增中激活脊髓神经胶质细胞的重要作用，众所周知，这些细胞可以增强和延长二阶脊柱感觉神经元对周围刺激的响应。因此，感觉途径中的多个位点可能具有类似类型的“主要”缺陷，或者尿路上皮中的主要缺陷可能会依次触发更近端部位的次级缺陷。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的信号传导途径，以及负责各种细胞 - 细胞相互作用的信号传导机制以及如何在FIC中改变这些机制。这些目标将使用多学科方法来实现，包括成像技术，分子生物学和释放发射机的测量。 AIM＃1将评估调节PBS/FIC中尿路上皮囊泡回收和发射器释放的细胞内机制。我们假设，响应机械或化学刺激的响应于尿路上皮的介体/信号传导因子的释放有助于诊断为FIC的猫的感觉症状。该目标将使用膜 - 覆盖染料的成像，以探索负责化学和机械诱发尿路上皮细胞中介质释放的机制。 AIM＃2将评估PBS/FIC中伞状细胞形态，信号传导和通信的基础机制。我们将使用完整的膀胱片和极化尿路上皮培养物来测量尿路上皮层之间顶端细胞性质的变化和细胞信号传导。 AIM＃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中的神经神经元相互作用。了解这些类型的变化所涉及的机制可能为开发PBS/IC临床管理的新目标提供重要见解。 公共卫生相关性：疼痛的膀胱综合征/间质性膀胱炎（PBS/IC）是一种慢性的，特发性疼痛的膀胱疼痛疾病，通常被描述为尿皮上的疾病（膀胱腔内衬里的上皮层）。猫的一种可比疾病称为猫肠间隙膀胱炎（FIC），几乎表现出人类PBS/IC的所有特征和症状。这是赠款的续签应用，我们确定fic紫菜皮对化学和物理刺激的敏感性增强，随后尿路上皮衍生的发射器释放增强。这些研究将研究这种类型的非神经元异常/痛觉过敏的机制。了解有助于和维持这些类型变化的机制可能为识别膀胱疾病（例如PBS/IC）的未来临床管理的新目标提供重要见解。