PNPase inhibition as an effective treatment for chronic bladder pain

PNPase 抑制可有效治疗慢性膀胱疼痛

• 批准号: 10580923
• 负责人: LORI A BIRDER
• 金额: $ 237.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-24 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580923
• 关键词: Acute; Acute Disease; Age; Animal Model; Animals; Antioxidants; Attenuated; Biological Markers; Bladder; Bladder Dysfunction; Blood specimen; Cells; Chronic; Chronic Disease; Chronic stress; Clinical; Cyclophosphamide; Data; Diagnosis; Disease; Enzymes; Epidemiology; Etiology; Exhibits; Flare; Free Radicals; Frustration; Functional disorder; Human; Hyperalgesia; Increased frequency of micturition; Individual; Inflammation; Innovative Therapy; Interstitial Cystitis; Knowledge; Lesion; Link; Measures; Mediating; Mediator of activation protein; Metabolism; Mitochondria; Modeling; Molecular; Morphology; Neuroglia; Nociception; Organ; Organelles; Oxidative Stress; Pain; Pain Disorder; Pathology; Patients; Persistent pain; Pharmaceutical Preparations; Pharmacology; Physiology; Plasma; Psychological Stress; Publishing; Purine Nucleoside Phosphorylase Inhibitor; Purine-Nucleoside Phosphorylase; Purines; Rattus; Reactive Oxygen Species; Reporting; Research; Rodent Model; Role; Sampling; Source; Spinal; Spinal Cord; Spinal Ganglia; Stress; Syndrome; Testing; Tissues; Urine; Validation; Viscera; Visceral pain; Water; antioxidant enzyme; base; bladder pain; cell injury; chronic painful condition; clinical efficacy; clinical practice; clinically relevant; comorbidity; daily pain; design; disorder prevention; disorder risk; effective therapy; exosome; experimental study; inhibitor; interdisciplinary approach; knock-down; metabolome; mitochondrial dysfunction; mitochondrial oxidative dysfunction; non-opioid analgesic; oxidative damage; pain sensitivity; pain signal; patient population; programs; purine analog; relating to nervous system; response; stem; therapeutic target; treatment response

Abstract: Chronic visceral pain disorders, such as interstitial cystitis/bladder pain syndrome (IC/BPS), are among the most difficult types of pain to treat, and response to treatment is often negligible. IC/BPS lacks a well-defined cause, is difficult to diagnose and to date, has no clear therapeutic target. Importantly, both psychological and oxidative stress have been shown to trigger a number of responses which can exacerbate such generalized pain syndromes and may do so by enhancing the effects of pro-nociceptive mediators and promoting oxidative damage. Chronic stress differs from acute or episodic stress as it leads to the persistent elevation of stress mediators that negatively impacts organ function in both animals and humans. Chronic stress increases the risk of disease/pathology and can itself result in hyperalgesia or pain in individuals predisposed to disease. More than half of patients with IC/BPS report daily or constant pain and urinary frequency, exacerbated by stressful circumstances- this exacerbation is termed a pain ‘flare’. While progress has been made to delineate the spinal circuits that gate pain signals emanating from the viscera, lack of a clear understanding of functional pain, their associated co-morbidities and a therapeutic target are a source of frustration for the clinician and patient. Because there are no effective treatments for IC/BPS, our research program is dedicated to discovering mechanisms mediating IC/BPS and applying that knowledge to target identification and validation. In this application, our plans for initial target identification and validation will use two distinct rodent models for IC/BPS which include a ‘bladder-centric’ model (cyclophosphamide-CYP) and a chronic stress model (water avoidance stress or WAS) model. While no available model attempts to mimic particular epidemiologic findings of IC/BPS patients, our findings in both models reveal similarities to human IC/BPS including changes in morphology and function of bladder neural and non-neuronal cells. In this regard, our newest preliminary experiments show that treatment of IC/BPS animals with a purine analog that increases uro-protective purines while simultaneously decreasing uro-damaging purines is effective at lowering pain sensitivity and reverses bladder dysfunction. Taken together, our research teams will use a multidisciplinary approach to validate a non-opioid-based target, namely purine nucleoside phosphorylase (PNPase), for the treatment of visceral pain disorders (e.g., IC/BPS). To achieve our objectives, in Aim 1, this project will determine validity of our target by assessing the role of PNPase in visceral pain using pharmacologic inhibitors in addition to using molecular approaches to knockdown PNPase and, in Aim 2, proof of concept for our target by measuring purines in exosomes isolated from IC/BPS and Hunner’s lesion patient samples to assess the role of PNPase as a contributor to visceral pain. Therapies that can protect mitochondria and reduce oxidative stress are likely to be important in terms of disease prevention. If successful, this therapy will challenge and shift current research and clinical practice paradigms.

抽象的： 慢性内脏疼痛障碍，例如间质性膀胱炎/膀胱疼痛综合征（IC/bps），是 治疗的最困难类型和对治疗的反应通常可以忽略不计。 IC/BPS缺乏定义明确的 原因很难诊断，并且迄今为止没有明确的治疗靶点。重要的是，心理和 氧化应激已被证明会触发许多反应，这些反应会加剧这种普遍的疼痛 综合征，可以通过增强促伤害性介体的影响并促进氧化作用来做到这一点。 损害。慢性应激与急性或发作压力不同，因为它导致压力的持续升高 对动物和人类的器官功能产生负面影响的介体。慢性压力增加了风险 疾病/病理学本身会导致易感疾病的个体的痛苦或疼痛。更多的 IC/BP的一半患者每天报告或持续的疼痛和尿频，这会受到压力的加剧 情况 - 这种加重被称为“耀斑”的痛苦。虽然已经取得了描述脊柱的进展 门疼痛的电路信号信号是从内脏发出的，对功能疼痛缺乏明确的了解 相关的合并症和治疗靶标是临床和患者沮丧的根源。 因为没有对IC/BP的有效治疗方法，所以我们的研究计划致力于发现 介导IC/BP并将这些知识应用于目标识别和验证的机制。在这个 应用，我们的初始目标识别和验证计划将使用两个不同的啮齿动物模型用于IC/BPS 其中包括“以膀胱为中心”模型（环磷酰胺-CYP）和慢性应激模型 压力或WAS）模型。尽管没有可用的模型尝试模仿IC/BPS的特定流行病学发现 患者，我们在这两个模型中的发现都揭示了与人类IC/BP的相似性，包括形态学的变化和 膀胱神经和非神经元细胞的功能。在这方面，我们最新的初步实验表明 用纯模拟对IC/BPS动物的处理，同时增加Uro保护嘌呤 减少URO的王子可有效降低疼痛敏感性并逆转膀胱功能障碍。 综上所述，我们的研究团队将使用多学科的方法来验证非阿片类药物的目标，即 即纯核磷酸化酶（PNPase），用于治疗内脏疼痛障碍（例如， IC/BP）。为了实现我们的目标，在AIM 1中，该项目将通过评估我们的目标有效性 PNPase在使用药物抑制剂的作用中，除了使用分子方法 敲除PNPase，在AIM 2中，通过测量孤立的外泌体中的王子来为我们的目标提供概念证明 从IC/BPS和Hunner的病变患者样本来评估PNPase作为内脏疼痛的促进的作用。 可以保护线粒体和减少氧化应激的疗法在疾病方面可能很重要 预防。如果成功，这种疗法将挑战并改变当前的研究和临床实践范例。