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

VEGF对泌尿科慢性盆腔疼痛综合征盆腔疼痛和排尿反射的调节作用

• 批准号: 9763111
• 负责人: Anna P Malykhina
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763111
• 关键词: Abdomen; Address; Affect; Afferent Neurons; Angiogenic Factor; Animal Model; Animals; Antibodies; Avastin; Behavioral; Biochemical; Biological Assay; Biological Markers; Bladder; Blood Vessels; Chronic; Chronic Prostatitis; Clinical; Clinical Data; Clinical Trials Design; Complex; Coupling; Data; Development; Disease; Electrophysiology (science); Endothelial Growth Factors Receptor; FDA approved; Filament; Frequencies; Functional disorder; Generations; Human; Hyperalgesia; Impairment; In Vitro; Inflammation; Interstitial Cystitis; Intravesical Instillation; Knowledge; Laboratories; Limb structure; Link; Lower urinary tract; Maintenance; Measures; Metabolic; Methods; Micturition Reflex; Motor; Motor Neurons; Mus; Nerve; Neural Pathways; Neurogenic Inflammation; Neuronal Plasticity; Neurons; Neuropilins; Nociception; Pain; Pain management; Paper; Pathway interactions; Patients; Pelvic Pain; Pelvis; Peripheral; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Play; Regulation; Role; Sensory; Severities; Sexual Dysfunction; Signal Transduction; Site; Spinal; Spinal Cord; Symptoms; Testing; Therapeutic; Treatment Factor; Urination; Urodynamics; Vascular Endothelial Growth Factors; Visceral; Visceral pain; Woman; afferent nerve; angiogenesis; awake; bladder pain; central sensitization; cholinergic; chronic pelvic pain; density; design; designer receptors exclusively activated by designer drugs; diagnostic biomarker; enhancing factor; experience; experimental study; innovation; lower urinary tract symptoms; men; minimally invasive; nerve supply; neurogenesis; neutralizing antibody; novel; novel therapeutics; pain sensation; prevent; receptor; response; sensory input; translational impact; translational study; urinary; urologic

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.

项目概要 泌尿科慢性盆腔疼痛综合征 (UCPPS) 是一种复杂的多因素疾病，其特征是 排尿和/或性功能障碍、内脏痛觉过敏和慢性盆腔疼痛 (CPP)。上一个动物 我们实验室的研究表明，周围神经源性炎症与中枢神经炎症一起 敏化在 UCPPS 症状的产生和维持中发挥作用。 MAPP 的最新研究 网络证实VEGF可能是UCPS的潜在尿液生物标志物之一。具体来说，患者 与健康对照相比，UCCPS 组的尿 VEGF 和 VEGF 受体水平显着升高。 此外，疼痛的严重程度与尿 VEGF 的增加显着相关，表明它可能有助于 作为临床上有用的 UCPPS 诊断标志物。尽管有这些新颖的临床数据，但其位点和机制 VEGF 在中枢神经系统中的作用，控制排尿，对外周和中枢神经元的兴奋性产生影响 神经支配下尿路（LUT）仍然未知。因此，机械参与的证明 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先前已被充分证实，但对其参与的了解却少之又少。 内脏痛的神经发生。我们是第一个提供直接证据证明膀胱内滴注 小鼠体内的 VEGF 促进感觉神经和运动神经密度显着增加，这与 尿动力学记录的逼尿肌过度活动和腹部敏感性增强。当前应用 建立在我们最初的发现的基础上，重点是确定 VEGF 调节神经的机制 支配下尿路的膀胱周围神经元和脊髓神经元的可塑性。还将探索潜力 VEGF 激活的膀胱伤害性（疼痛相关）通路与排尿反射的交叉效应， 正如在 UCPPS 患者中观察到的那样。其他研究将使用现有的方法来测试药理学方法 VEGF 中和抗体，用于评估其限制疼痛感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，这项研究将产生新颖的、 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 为患有以下疾病的患者开发个体化治疗方法所必需的知识差距 UCPS。