Cross Organ Mechanisms in Chronic Pelvic Pain

慢性盆腔疼痛的跨器官机制

• 批准号: 10656603
• 负责人: Frank Fu-sheng Tu
• 金额: $ 72.35万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656603
• 关键词: Acceleration; Accounting; Acute; Address; Afferent Neurons; Animals; Anti-Inflammatory Agents; Biological; Biological Assay; Bladder; Blood; Brain; Chronic; Clinical; Collection; Communication; Data; Development; Distress; Dysmenorrhea; Early Intervention; Electroencephalography; Equipment and supply inventories; Event; Event-Related Potentials; Exhibits; Follow-Up Studies; Functional disorder; Health; Home; Hypersensitivity; Impairment; Inflammation; Inflammatory; Inflammatory Response; Interstitial Cystitis; Irritable Bowel Syndrome; Knowledge; Leukocytes; Longitudinal Studies; Longitudinal, observational study; Measurement; Measures; Mediating; Methods; Mission; Natural History; Neurobiology; Neurologic; Non-Visceral; Organ; Outcome; Pain; Pain Disorder; Pain Free; Participant; Pathway interactions; Patients; Pelvic Pain; Pelvis; Perception; Persons; Phenotype; Pilot Projects; Populations at Risk; Prevention; Prevention strategy; Prospective Studies; Psychophysics; Quality of life; Questionnaires; Recording of previous events; Risk; Sampling; Sensory; Severities; Spinal; Symptoms; System; TLR4 gene; Testing; Time; United States National Institutes of Health; Vertebral column; Visceral; Whole Blood; Woman; aged; bladder pain; care costs; chronic pain; chronic pain patient; chronic painful condition; chronic pelvic pain; cohort; cost; density; effective therapy; endometriosis; experience; follow-up; health assessment; high risk; innovation; mindfulness meditation; multimodality; neural; neuromechanism; pain chronification; pain outcome; pain sensitivity; pain symptom; predicting response; prevent; productivity loss; prospective; psychologic; public health priorities; reproductive; response; screening; symptomatology; systemic inflammatory response; two-dimensional; virtual; young woman

Chronic pelvic pain (CPP) disorders cause significant distress and often lack effective treatments. Although dysmenorrhea is closely associated with 80% of cases of CPP, little is known about why only some women with menstrual pain go on to develop conditions like interstitial cystitis/bladder pain syndrome, irritable bowel syndrome, or endometriosis. Intriguingly, 20% of dysmenorrhea sufferers (without chronic pain) display a key feature of many CPP states, bladder hypersensitivity on noninvasive bladder filling, and appear on pilot studies at higher risk of CPP in one year. In this team’s prior studies, women with the dysmenorrhea with bladder pain phenotype (DYSB) also exhibit greater somatic symptom burden, experimental pain hypersensitivity, and psychological dysregulation—features found in many chronic pain patients. As little is known about the acute to CPP transition, this renewal application seeks to track pelvic pain symptomatology prospectively in DYSB women and to expand those initial mechanistic studies. Aim 1 is a two-year longitudinal study of 1050 young women oversampled for dysmenorrhea to find 150 DYSB cases and establish their risk trajectory for CPP symptoms vs. those with only dysmenorrhea (DYS only = 750) and healthy controls (HC = 150). Along with a virtual bladder filling screening test, other patient health factors potentially predicting development of CPP will be captured, including overall pelvic experiences and general sensory sensitivity. Aim 2 will investigate 100 DYSB and 100 controls (DYS only and HC) on two dimensions of CPP mechanistically—bladder hypersensitivity and multimodal hypersensitivity (a composite of experimentally evoked responses to nonvisceral quantitative sensory tests [QST]). Electroencephalography-based studies will further investigate which neurological mechanisms (i.e. ascending neural hyperexcitability, descending inhibition, and neural oscillations) underlie these two components and predict one-year worsening of CPP symptoms. Aim 3 studies whether another key mechanism of pain sensitization, Toll-like Receptor-4 inflammatory reactivity, influences CPP progression, using an integrated whole-blood collection and leukocyte culture system. This renewal application significantly extends this discovery of an at-risk phenotype by providing a method for expanding screening and characterizing reversible mechanisms. This essential followup study utilizes innovative combinations of QST with EEG measurements of brain activity to identify the mechanisms responsible for CPP-related-sensory abnormalities, alongside measures of systemic inflammatory reactivity that are strongly implicated in sensory hypersensitivity. Notably, if these are confirmed, candidate early interventions already exist to modulate these mechanisms, including mindfulness meditation and consistent anti-inflammatory use for dysmenorrhea. Successful completion of these studies would accelerate efforts to prevent the transition from acute to chronic pelvic pain, a major public health priority.

慢性骨盆疼痛（CPP）疾病会引起严重的困扰，并且常常缺乏有效的治疗方法。虽然 痛经与80％的CPP病例密切相关，为什么只有某些女性才知道 月经疼痛继续发展，例如诸如膀胱炎/膀胱疼痛综合征，肠易激 综合征或子宫内膜异位症。有趣的是，20％的痛经患者（无慢性疼痛）显示钥匙 许多CPP状态的特征，非侵入性膀胱填充的膀胱超敏反应，并出现在试点研究中 一年内CPP的风险更高。在该团队先前的研究中，患有痛苦的妇女患有膀胱疼痛 表型（DYSB）还表现出更大的体细胞症状伯恩，实验性疼痛超敏反应和 心理失调 - 许多慢性疼痛患者中发现的功能。关于急性的知之甚少 CPP过渡，此更新应用旨在在DYSB中前瞻性地跟踪骨盆疼痛症状 妇女并扩大那些初步的机械研究。 AIM 1是一项为期两年的1050年轻的纵向研究 妇女因痛经而过采样，以查找150例DYSB病例，并为CPP建立风险轨迹 症状与只有痛经（仅DYS = 750）和健康对照（HC = 150）的症状。以及 虚拟膀胱填充筛查测试，其他患者健康因素可能预测CPP的发展 被捕获，包括整体骨盆经历和一般的感觉灵敏度。 AIM 2将调查100 在CPP的两个维度上，DYSB和100个对照（仅DYS和HC）机械上的两个维度 高敏性和多模式超敏反应（实验诱发的反应的综合 非守护定量感觉测试[QST]）。基于脑电图的研究将进一步研究 哪种神经系统机制（即升高神经元过度刺激性，降低抑制作用和神经元 振荡）这是这两个组成部分的基础，并预测了CPP症状的一年愿望。 AIM 3研究 疼痛敏感性的另一种关键机制，Toll样受体-4炎症反应性是否会影响 CPP进展，使用整体血管收集和白细胞培养系统。这个更新 应用程序通过提供一种方法来大大扩展了这种处于风险表型的发现 扩大筛查和表征可逆机制。这项基本的后续研究利用 QST与脑活动的EEG测量的创新组合，以识别机制 负责与CPP相关的 - 感官异常，以及全身性炎症的测量 反应性与感觉超敏反应有关。值得注意的是，如果确认这些， 候选人已经存在以调节这些机制的早期干预措施，包括正念冥想 以及持续的抗炎作用用于痛经。这些研究成功完成将 加快努力，以防止从急性到慢性骨盆疼痛的过渡，这是一个主要的公共卫生优先事项。

项目成果

Identification of experimental bladder sensitivity among dysmenorrhea sufferers.

• DOI: 10.1016/j.ajog.2018.04.030
• 发表时间: 2018-07
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: Hellman KM;Datta A;Steiner ND;Kane Morlock JN;Garrison EF;Clauw DJ;Tu FF
• 通讯作者: Tu FF

Somatic symptoms in women with dysmenorrhea and noncyclic pelvic pain.

患有痛经和非周期性盆腔疼痛的女性的躯体症状。

• DOI: 10.1007/s00737-018-0823-4
• 发表时间: 2018-10
• 期刊: Archives of women's mental health
• 作者: Zuckerman RM;Silton RL;Tu FF;Eng JS;Hellman KM
• 通讯作者: Hellman KM

Cortical Mechanisms of Visual Hypersensitivity in Women at Risk for Chronic Pelvic Pain.

有慢性盆腔疼痛风险的女性视觉过敏的皮质机制。

• DOI: 10.1101/2020.12.03.20242032
• 发表时间: 2021
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Kmiecik,MatthewJ;Tu,FrankF;Silton,RebeccaL;Dillane,KatlynE;Roth,GenevieveE;Harte,StevenE;Hellman,KevinM
• 通讯作者: Hellman,KevinM

Clinical profile of comorbid dysmenorrhea and bladder sensitivity: a cross-sectional analysis.

共病痛经和膀胱敏感性的临床特征：横断面分析。

• DOI: 10.1016/j.ajog.2019.12.010
• 发表时间: 2020
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: Tu,FrankF;Datta,Avisek;Atashroo,Diana;Senapati,Sangeeta;Roth,Genevieve;Clauw,DanielJ;Hellman,KevinM
• 通讯作者: Hellman,KevinM

Generalized sensory sensitivity is associated with comorbid pain symptoms: a replication study in women with dysmenorrhea.

全身感觉敏感性与共病疼痛症状相关：一项针对痛经女性的重复研究。

• DOI: 10.1097/j.pain.0000000000002676
• 发表时间: 2023
• 期刊: Pain
• 影响因子: 7.4
• 作者: Schrepf,Andrew;Hellman,KevinM;Bohnert,AmyM;Williams,DavidA;Tu,FrankF
• 通讯作者: Tu,FrankF