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

基本信息

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
项目类别：
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

项目摘要

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）。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 MAPP 最近的研究表明，敏化在 UCPPS 症状的产生和维持中发挥着重要作用。网络证实 VEGF 可能是 UCPPS 患者的潜在尿液生物标志物之一。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，但其位点和机制仍然存在。 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，机械性参与的证明。 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 治疗缓解 LUTS 和膀胱疼痛在 UCPPS 中的作用的临床试验。 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。我们是第一个提供膀胱内灌注的直接证据的小组。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增强的腹部敏感性当前的应用。建立在我们最初的发现的基础上，重点是确定 VEGF 调节神经的机制它还将探索支配下尿路的膀胱周围和脊髓神经元的可塑性。 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药理学方法进行测试。 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总的来说，这项研究将产生新颖的、膀胱疼痛和排尿功能障碍的动物模型。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需的知识差距 UCPS。