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： 慢性内脏疼痛疾病，例如间质性膀胱炎/膀胱疼痛综合征（IC/BPS） 最难治疗的疼痛类型，并且对治疗的反应通常可以忽略不计。 病因难以诊断，迄今为止还没有明确的治疗目标，重要的是，无论是心理上还是心理上。 氧化应激已被证明会引发多种反应，从而加剧全身疼痛 综合征，可能是通过增强促伤害性介质的作用和促进氧化来实现的 慢性压力不同于急性或偶发性压力，因为它会导致压力持续升高 对动物和人类的器官功能产生负面影响的介质慢性压力会增加风险。 疾病/病理学的影响，并且其本身可以导致易患疾病的个体痛觉过敏或疼痛。 超过一半的 IC/BPS 患者报告每天或持续疼痛和尿频，并因压力而加剧 在这种情况下，这种加剧被称为疼痛“耀斑”，尽管在描绘脊柱方面已经取得了进展。 控制从内脏发出的疼痛信号的电路，缺乏对功能性疼痛的清晰了解， 相关的合并症和治疗目标是临床医生和患者沮丧的根源。 由于 IC/BPS 没有有效的治疗方法，我们的研究项目致力于发现 调解 IC/BPS 的机制并将该知识应用于目标识别和验证。 应用程序中，我们的初始目标识别和验证计划将使用两种不同的 IC/BPS 啮齿动物模型 其中包括“以膀胱为中心”的模型（环磷酰胺-CYP）和慢性应激模型（避免饮水） 虽然没有可用的模型试图模拟 IC/BPS 的特定流行病学结果。 患者，我们在这两个模型中的发现揭示了与人类 IC/BPS 的相似之处，包括形态和功能的变化 膀胱神经细胞和非神经细胞的功能在这方面，我们最新的初步实验表明： 用嘌呤类似物治疗 IC/BPS 动物，同时增加泌尿保护性嘌呤 减少对泌尿系统有损害的嘌呤可有效降低疼痛敏感性并逆转膀胱功能障碍。 总的来说，我们的研究团队将使用多学科方法来验证非阿片类药物的目标， 即嘌呤核苷磷酸化酶（PNPase），用于治疗内脏疼痛疾病（例如， IC/BPS）。为了实现我们的目标，在目标 1 中，该项目将通过评估来确定我们目标的有效性。 除了使用分子方法外，还使用药物抑制剂研究 PNPase 在内脏疼痛中的作用 敲低 PNPase，并在目标 2 中通过测量分离的外泌体中的嘌呤来证明我们的目标的概念 从 IC/BPS 和 Hunner 病变患者样本中提取 PNPase 来评估 PNPase 导致内脏疼痛的作用。 可以保护线粒体并减少氧化应激的疗法可能对疾病很重要 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式。