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: 10166603
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166603
• 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 chronic pelvic pain syndrome

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.

项目摘要 泌尿科慢性骨盆疼痛综合征（UCPPS）是一种复杂而多因素的疾病 通过空隙和/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 我们实验室的研究确定，周围神经源性感染与中央 致敏性在UCPPS符号的生成和维护中起作用。 MAPP的最新研究 网络证实，VEGF可能是UCPP的潜在尿生物标志物之一。具体来说，患者 UCCP的尿液VEGF和VEGF受体水平明显高于健康对照。 此外，疼痛的严重程度与增加的VEGF显着相关，这表明它可能服务 作为UCPPS的临床上有用的诊断标记。尽管有这种新颖的临床数据，但地点和机制 CNS中心中的VEGF作用控制排尿，对周围和中央神经元兴奋的影响 支配下尿路（LUT）仍然未知。因此，演示机械参与 VEGF在膀胱疼痛和空隙功能障碍中的作用将提供科学的理由和“概念证明”数据 用于设计抗VEGF治疗的临床试验，以减轻UCPPS中的LUT和膀胱疼痛。而角色 血管生成中VEGF的vegf以前已经建立了良好，对其参与的了解少得多 内脏疼痛的神经发生。我们是第一个提供直接证据表明静脉注入 小鼠中的VEGF促进了感觉神经的密度显着增加，这是相关的 随着尿动力学记录的迫害者的过度活动性和增强的腹部灵敏度。当前申请 建立在我们的初步发现的基础上，并专注于确定VEGF调节中性的机制 膀胱外周和脊柱神经元的可塑性支配下尿路。它也将探索潜力 VEGF激活的膀胱伤害感受（疼痛相关）途径与排尿反射的交叉效应， 如UCPP患者所观察到的。其他研究将使用可用的 VEGF中和抗体，以评估其潜力，以限制疼痛感觉并恢复膀胱功能 膀胱疼痛和空隙功能障碍的翻译动物模型。总体而言，这项研究将导致新颖 可解释的数据扩展了以假设驱动的完成方式扩展MAPP的最新研究，并将填补 为患者开发个性化治疗方法所需的知识差距 UCPPS。

项目成果

Relationship of Bladder Pain With Clinical and Urinary Markers of Neuroinflammation in Women With Urinary Urgency Without Urinary Incontinence.

• DOI: 10.1097/spv.0000000000000951
• 发表时间: 2021-02-01
• 期刊: Female pelvic medicine & reconstructive surgery
• 影响因子: 1.6
• 作者: Soriano A;Andy U;Hassani D;Whitmore K;Harvie H;Malykhina AP;Arya L
• 通讯作者: Arya L

Functional constipation induces bladder overactivity associated with upregulations of Htr2 and Trpv2 pathways.

• DOI: 10.1038/s41598-020-80794-0
• 发表时间: 2021-01-13
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Iguchi N;Carrasco A Jr;Xie AX;Pineda RH;Malykhina AP;Wilcox DT
• 通讯作者: Wilcox DT

Relationship of Pain Catastrophizing With Urinary Biomarkers in Women With Bladder Pain Syndrome.

• DOI: 10.1097/spv.0000000000001041
• 发表时间: 2021-12-01
• 期刊: Female pelvic medicine & reconstructive surgery
• 影响因子: 1.6
• 作者: Soriano A;Allen A;Malykhina AP;Andy U;Harvie H;Arya L
• 通讯作者: Arya L

Marijuana, Alcohol, and ED: Correlations with LUTS/BPH.

• DOI: 10.1007/s11934-020-01031-9
• 发表时间: 2021-02-08
• 期刊: Current urology reports
• 影响因子: 2.6
• 作者: Lloyd GL;Wiesen B;Atwell M;Malykhina A
• 通讯作者: Malykhina A