Novel biomarkers and pathways of persistent endometriosis-associated pain across the life course

摘要。子宫内膜异位症是一种慢性炎症性疾病， 子宫外的组织，往往表现为疼痛和不孕，影响约10%的生殖 老年妇女。虽然有些妇女对激素治疗或手术治疗反应良好，但其他妇女则没有， 被持续的或恶化的疼痛所困扰。许多患者的生活受到严重影响， 子宫内膜异位症相关性盆腔疼痛（EAPP）经历了从急性到持续性疼痛的转变，通常在早期 以及随后的症状恶化。一旦疼痛变得持续，它往往是难治性的电流 治疗，并可能进一步发展到包括衰弱的共病症状，如背部，膀胱和肠道 疼痛，以及广泛的疼痛和疲劳。鉴定与持续性和/或慢性炎症相关的预后生物标志物 难治性EAPP将允许在脆弱患者中进行治疗和干预的战略选择， 疼痛变得根深蒂固。我们的总体假设是，神经免疫/炎症标记物可以帮助 识别有发生持续性和/或伤害性疼痛风险的女性。具体来说，我们假设， 神经免疫/炎症活动有助于EAPP的出现和持续， 青春期，以及成年人的伤害性疼痛的发展。我们的初步分析表明， 炎症和神经免疫途径与更严重的症状相关， 转变为持续性和/或难治性疼痛。在本提案中，我们将利用现有的纵向 从年轻女性中收集的问卷数据和库存生物标本（连续血液和腹膜液） 参加妇女健康研究25年以上：从青春期到成年（A2 A），以评估 EAPP的出现。此外，按照协调一致的方案，我们将收集血液样本、腹膜液和 一组新的成年女性的功能性MRI，这些女性在青春期开始患有EAPP， 在密歇根大学（UM）接受手术和非手术治疗，以评估 伤害性EAPP的标志物。我们将应用创新的蛋白质组学平台（基础科学部分）， 显示出高重现性，可以同时测量> 7，000种蛋白质。详细纵向 基于自我报告的糖尿病相关症状评估（临床/翻译部分） 疼痛（两项研究）和fMRI（仅UM队列），以及两项研究之间的生物标志物定量将协调一致 以确定与持续性EAPP的稳健关联。通过利用全身和局部生物标志物， 随着时间的推移，结合详细的疼痛评估，该项目是唯一准备确定生物标志物 与持续性脊髓炎相关疼痛和伤害性疼痛的出现相关， 了解导致盆腔疼痛的潜在机制。

ABSTRACT. Endometriosis is a chronic inflammatory condition defined by the presence of endometrial-like tissue outside the uterus that often presents with pain and infertility, affecting approximately 10% of reproductive aged women. While some women respond well to hormonal therapy or surgical treatment, others do not and are plagued with continued or worsening pain. Many patients whose lives are substantially impacted by endometriosis associated pelvic pain (EAPP) experienced a transition from acute to persistent pain, often early in life, and subsequent worsening of symptoms. Once pain becomes persistent, it is often refractory to current treatments and may further evolve to include debilitating comorbid symptoms such as back, bladder and bowel pain, as well as widespread pain and fatigue. Identifying prognostic biomarkers associated with persistent and/or refractory EAPP would allow for strategic selection of treatments and interventions in vulnerable patients before pain becomes entrenched. Our overarching hypothesis is that neuroimmune/inflammatory markers can help identify women at risk for developing persistent and/or nociplastic pain. Specifically, we hypothesize that neuroimmune/inflammatory activity contributes to both the emergence and persistence of EAPP during adolescence, as well as the development of nociplastic pain in adults. Our preliminary analyses suggest that inflammatory and neuroimmune pathways are associated with more severe symptoms and may be implicated in the transition to persistent and/or refractory pain. In this proposal, we will leverage existing longitudinal questionnaire data and banked biospecimens (serial blood and peritoneal fluid) collected from females younger than 25 years participating in the Women’s Health Study: From Adolescence to Adulthood (A2A) to evaluate the emergence of EAPP. Further, following harmonized protocols we will collect blood samples, peritoneal fluid, and functional MRIs from a new cohort of adult women with established EAPP that began in adolescence who are undergoing both surgical and non-surgical therapies at the University of Michigan (UM) in order to evaluate markers of nociplastic EAPP. We will apply an innovative proteomics platform (basic science component) that has shown high reproducibility and can simultaneously measure >7,000 proteins. Detailed longitudinal assessment of endometriosis-associated symptoms (clinical/translational component), based on self-reported pain (both studies) and fMRI (UM cohort only), and biomarker quantification will be harmonized between the two cohorts to determine robust associations with persistent EAPP. By leveraging systemic and local biomarkers in combination with detailed pain assessment over time, this project is uniquely poised to identify biomarkers associated with persistent endometriosis-associated pain and emergence of nociplastic pain to advance our understanding of the underlying mechanisms that contribute to pelvic pain.