Mechanistic Characterization of Uterine Pain (M-CUP) to improve diagnosis and treatment for dysmenorrhea

子宫疼痛 (M-CUP) 的机制表征可改善痛经的诊断和治疗

• 批准号: 10011893
• 负责人: Kevin Hellman
• 金额: $ 60万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011893
• 关键词: Address; Affect; Age; Algorithms; Anaerobic Bacteria; Anti-Inflammatory Agents; Biological Availability; Blood; Categories; Child; Contrast Media; Crossover Design; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dysmenorrhea; Ensure; Event; Failure; Foundations; Generations; Goals; Health; High Pressure Liquid Chromatography; Hypoxemia; Image; Imaging Techniques; Impairment; Ischemia; Knowledge; Leiomyoma; Link; MRI Scans; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Menstruation; Methods; Modality; Muscle Cramp; Myometrial; Naproxen; National Institute of Child Health and Human Development; Operative Surgical Procedures; Pain; Pain Disorder; Participant; Pathology; Patient Self-Report; Patients; Pelvis; Perfusion; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Physiological Processes; Physiology; Placebo Control Effect; Placebos; Plant Roots; Premature Labor; Productivity; Prostaglandin Inhibition; Quality of life; Randomized; Reporting; Reproductive Process; Research; Resistance; Respiration; Risk; Risk Factors; Serum; Source; Spectrum Analysis; Structure; Testing; Therapeutic; Time; Translations; Uterine Contraction; Uterine Diseases; Uterine Monitoring; Uterus; Woman; absorption; base; chronic pelvic pain; clinically significant; cohort; conventional therapy; disability; drug candidate; drug discovery; endometriosis; experience; human data; idiopathic infertility; improved; myometrium; non-invasive imaging; pain perception; pain relief; personalized medicine; prevent; programs; reproductive; response; spontaneous pain; targeted treatment; tissue oxygenation; tool; treatment strategy; uterine contractility; uterus endometriosis

Due to a lack of noninvasive tools to study uterine physiology, the root causes of menstrual cramping pain within primary dysmenorrhea and secondary dysmenorrhea (leiomyoma, endometriosis, adenomyosis) remain unknown. This pain does not respond to typical over-the-counter anti-inflammatories in 15% of women and is a leading risk factor for developing challenging chronic pelvic pain disorders. In order to guide drug discoveries and create personalized treatment approaches, it is essential to unveil the underlying mechanisms of dysmenorrhea. Our research program has focused on key gaps in our knowledge of uterine physiology, such as the contributions of uterine contractions, perfusion, and oxygenation to menstrual pain. Although these factors are strongly implicated in this debilitating pain disorder, confirmatory human data is still needed. Such research would be quite timely, as numerous drug candidates targeting these potential mechanisms already exist. Our collaborative team has developed MRI-based tools to noninvasively and dynamically measure uterine contractions, perfusion, relative tissue oxygenation, and metabolites indicative of anaerobic respiration. We have also pioneered methods that link spontaneous pain report to simultaneous uterine events. Together, these methods will allow us to evaluate the contribution of contractility, perfusion, or hypoxemia to menstrual pain. Notably, our preliminary data supports our central hypothesis that menstrual pain is associated with different phenotypes involving myometrial hypercontractility, impaired uterine perfusion, uterine hypoxemia, or a non-uterine source. Since understanding how current anti-inflammatory medications relieve or prevent pain (and why they fail) is valuable for the development of improved treatment strategies, we will also investigate the effects of naproxen on uterine physiology in women with menstrual pain. To test our hypothesized contributions of altered uterine muscle activity, perfusion, and oxygenation on pain, we propose: Aim 1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI sequences of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. A cohort of women with leiomyoma and endometriosis will also be analyzed to evaluate the contribution of myometrial activity, perfusion, and oxygenation in women with structurally identifiable conditions. Aim 2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. Preliminary data suggests unresolved myometrial activity and inadequate naproxen absorption are associated with insufficient pain relief. Evaluating the naproxen-dependent effects of uterine physiology will provide a foundation for diagnostic tests to indicate relevant personalized treatment for patients that have failed conventional treatments. Further translation of these studies could advance mechanisms for discovery in other chronic pelvic pain conditions and uterine disorders such as idiopathic preterm labor and unexplained infertility.

由于缺乏研究子宫生理学的无创工具，因此月经限制疼痛的根本原因 在原发性痛经和继发性痛经（平滑肌瘤，子宫内膜异位症，子宫肌症）中仍然存在 未知。这种疼痛对15％的妇女的典型非处方抗炎作用没有反应，是 发展挑战性慢性骨盆疼痛障碍的领先危险因素。为了指导毒品发现 并创建个性化的治疗方法，必须揭示 痛经。我们的研究计划的重点是我们对子宫生理学知识的关键差距， 作为子宫收缩，灌注和氧合对月经疼痛的贡献。虽然这些 因素在这种使人衰弱的疼痛障碍中很大，仍然需要确认性人类数据。这样的 研究将是相当及时的，因为已经针对这些潜在机制的众多候选药物 存在。我们的协作团队已经开发了基于MRI的工具来非侵入性和动态测量 子宫收缩，灌注，相对组织氧合和代谢物表示厌氧呼吸。 我们还开创了将自发疼痛报告与同时子宫事件联系起来的方法。一起， 这些方法将使我们能够评估收缩力，灌注或低氧血症对月经的贡献 疼痛。值得注意的是，我们的初步数据支持我们的中心假设，即月经疼痛与 不同的表型，涉及子宫肌层超额收缩，子宫灌注受损，子宫低氧血症或 非户外来源。由于了解当前的抗炎药如何缓解或预防疼痛 （以及为什么失败）对于制定改进的治疗策略很有价值，我们还将调查 萘普生对月经疼痛女性子宫生理学的影响。测试我们的假设 我们提出：目标1：AIM 1： 表征与肌层活性损伤相关的月经疼痛表型， 灌注和/或氧合。子宫的连续MRI序列将与 同时测量健康女性的自我报告的疼痛以及经历月经疼痛的疼痛。一个 还将分析与平滑肌瘤和子宫内膜异位症的妇女队列一起评估 具有结构可识别的妇女的肌层活性，灌注和氧合。目标2： 评估萘普生对相对于肌层活性，灌注和/或氧合的影响 缓解疼痛。初步数据表明未解决的肌层活性和萘普生吸收不足 与疼痛缓解不足有关。评估子宫生理的萘普生依赖性作用将 为诊断测试提供基础，以指示失败的患者相关的个性化治疗 常规治疗。这些研究的进一步翻译可以推进其他发现的机制 慢性骨盆疼痛状况和子宫疾病，例如特发性早产和无法解释的不育症。