Regulation of pelvic pain and micturition reflex by VEGF in urological chronic pelvic pain syndrome

项目摘要 泌尿系慢性盆腔疼痛综合征（UCPPS）是一种复杂的多因素疾病， 排尿和/或性功能障碍、内脏痛觉过敏和慢性骨盆疼痛（CPP）。以前的动物 我们实验室的研究表明，外周神经源性炎症与中枢神经系统炎症一起， 致敏在UCPPS症状的产生和维持中起作用。MAPP的最新研究 网络证实VEGF可能是UCPPS潜在的尿生物标志物之一。具体来说，患者 UCCPS患者的尿VEGF和VEGF受体水平显著高于健康对照组。 此外，疼痛的严重程度与尿VEGF的增加显著相关，这表明它可能有助于 作为临床上有用的UCPPS诊断标志物。尽管有这些新的临床数据，但研究发现， VEGF在控制排尿的CNS中枢中的作用，对外周和中枢神经元兴奋性的影响 下尿路（LUT）的神经支配仍然未知。因此，机械参与的示范 VEGF在膀胱疼痛和排尿功能障碍中的作用将提供科学依据和"概念验证"数据 设计抗VEGF治疗的临床试验，以减轻UCPPS中的LUTS和膀胱疼痛。虽然角色 VEGF在血管生成中的作用以前已经很好地建立，但关于其参与血管生成的作用知之甚少。 内脏痛的神经发生我们是第一个提供直接证据的小组， VEGF在小鼠中促进感觉和运动神经密度的显著增加， 尿动力学记录逼尿肌过度活动和腹部敏感性增强。当前应用程序 建立在我们最初的发现，并集中在确定VEGF调节神经元的机制， 支配下尿路的膀胱外周和脊髓神经元的可塑性。它还将探索潜力 VEGF激活的膀胱伤害感受（疼痛相关）通路与排尿反射的交叉效应， 如在UCPPS患者中观察到的。其他研究将使用现有的药物方法测试药理学方法。 使用VEGF中和抗体评估其限制疼痛感觉和恢复膀胱功能的潜力 膀胱疼痛和排尿功能障碍的转化动物模型。总的来说，这项研究将产生新的， 可解释的数据，以假设驱动的互补方式扩展了最近的MAPP研究，并将填补 为患者制定个性化治疗方法所需的知识差距 UCPPS。

PROJECT SUMMARY Urological Chronic Pelvic Pain Syndrome (UCPPS) is a complex and multifactorial disorder characterized by voiding and/or sexual dysfunction, visceral hyperalgesia, and chronic pelvic pain (CPP). Previous animal studies from our laboratory established that peripheral neurogenic inflammation together with central sensitization play a role in generation and maintenance of UCPPS symptoms. Recent study from the MAPP network confirmed that VEGF could be one of the potential urinary biomarkers of UCPPS. Specifically, patients with UCCPS had significantly higher levels of urinary VEGF and VEGF receptors than healthy controls. Additionally, pain severity was significantly associated with increased urinary VEGF suggesting that it may serve as a clinically useful diagnostic marker for UCPPS. Despite this novel clinical data, the sites and mechanisms of VEGF action in the CNS centers controlling micturition, effects on excitability of peripheral and central neurons innervating the lower urinary tract (LUT) are still unknown. Therefore, demonstration of mechanistic involvement of VEGF in bladder pain and voiding dysfunction would provide scientific justification and “proof-of-concept” data for designing clinical trials of anti-VEGF treatments to alleviate LUTS and bladder pain in UCPPS. While the role of VEGF in angiogenesis has been previously well established, much less is known about its participation in neurogenesis of visceral pain. We were the first group to provide direct evidence that intravesical instillation of VEGF in mice promoted a significant increase in density of both sensory and motor nerves, which was associated with urodynamically recorded detrusor overactivity and enhanced abdominal sensitivity. Current application builds upon our initial findings, and is focused on determining the mechanisms by which VEGF modulates neural plasticity of bladder peripheral and spinal neurons innervating the lower urinary tract. It will also explore potential cross-effects of the VEGF-activated bladder nociceptive (pain-associated) pathways with the micturition reflex, as observed in patients with UCPPS. Additional studies will test pharmacological approaches using available VEGF neutralizing antibodies to evaluate their potential to limit pain sensation and restore bladder function using translational animal models of bladder pain and voiding dysfunction. Overall, the study will result in novel, interpretable data that expands recent MAPP studies in a hypothesis-driven complementary fashion, and will fill the knowledge gap necessary for the development of individualized therapeutic approaches for patients with UCPPS.