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

抽象的。子宫内膜异位症是一种慢性炎症性疾病，其定义是子宫内膜样变。 子宫外的组织，通常表现为疼痛和不孕，影响大约10%的生殖 年迈的女性。虽然一些女性对激素治疗或手术治疗反应良好，但另一些女性却不是，现在也是 被持续的或恶化的疼痛所困扰。许多生活受到严重影响的患者 子宫内膜异位症相关性盆腔疼痛(EAPP)经历了从急性疼痛到持续性疼痛的过渡，通常是早期的 在生活中，以及随后症状的恶化。疼痛一旦持续，往往对电流难以承受。 治疗，并可能进一步发展到包括虚弱的共病症状，如背部，膀胱和肠道 疼痛，以及广泛的疼痛和疲劳。确定与持久性和/或 难治性EAPP将允许在之前对脆弱患者进行治疗和干预的战略性选择 疼痛变得根深蒂固。我们的主要假设是神经免疫/炎症标记物可以帮助 确定有发生持续性和/或肿瘤性疼痛的风险的女性。具体地说，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，以及成人肿瘤性疼痛的发展。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有关，并可能与 向持续性和/或顽固性疼痛的过渡。在本提案中，我们将利用现有的纵向 从年轻女性收集的问卷数据和储存的生物检验品(连续血液和腹腔液) 参与妇女健康研究：从青春期到成年期(A2A)超过25年，以评估 EAPP的出现。此外，根据协调协议，我们将采集血液样本、腹腔液和 来自一组新的成年女性的功能磁共振成像，这些成年女性从青春期开始就有EAPP，她们是 在密歇根大学(UM)接受手术和非手术治疗，以评估 恶性EAPP的标志物。我们将应用一个创新的蛋白质组学平台(基础科学部分)， 具有很高的重复性，可以同时测量&gt；7,000个蛋白质。详细的纵向 基于自我报告的子宫内膜异位症相关症状评估(临床/翻译部分) 疼痛(两项研究)和功能磁共振成像(仅限UM队列)，以及生物标记物量化将在两者之间协调 队列以确定与持续性EAPP的可靠关联。通过利用系统和局部生物标记物 随着时间的推移，结合详细的疼痛评估，该项目是唯一能够确定生物标记物的项目 与持续性子宫内膜异位症相关的疼痛和肿瘤性疼痛的出现相关，以促进我们的 了解导致骨盆疼痛的潜在机制。

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.