Metabolomic profiling of adolescent endometriosis

摘要 子宫内膜异位症是一种使人衰弱的疾病，影响全球2亿妇女，造成严重疼痛， 不孕虽然超过50%的成年子宫内膜异位症患者在青春期报告疼痛发作，但大多数 子宫内膜异位症的女性平均延迟诊断7年， 手术可视化的诊断标准，导致疼痛延长和生活质量下降。因此，在本发明中， 迫切需要鉴定新的、非侵入性的子宫内膜异位症生物标志物，这是NICHD之一。 与子宫内膜异位症相关的研究目标。子宫内膜异位症的早期诊断， 青春期和青年期，可能会导致早期干预和改善临床结果。然而，在这方面， 对青少年子宫内膜异位症的病理生理学和分子特征知之甚少。 青春期子宫内膜异位症通常表现为严重的盆腔疼痛和浅表腹膜病变， 与成人诊断的子宫内膜异位症不同，后者通常表现为疼痛、不孕和深度纤维化 病变此外，我们的初步数据显示，约30%的青少年子宫内膜异位症患者患有 尽管接受了术后激素治疗，但术后盆腔疼痛仍持续或复发， 导致反复手术最近，我们报道了子宫内膜异位症患者血CA125升高， 在成人中诊断，在患有子宫内膜异位症的青少年中没有升高。青春期诊断的子宫内膜异位症 与成人诊断的子宫内膜异位症相比，可能具有不同的分子表型，这可能需要 不同的诊断和治疗策略。本申请的目的是识别新（1）血液 与青少年子宫内膜异位症相关的代谢组学特征和（2）腹腔液代谢组学标记物 预示术后持续疼痛。代谢产物是细胞活动的下游产物 受基因组调控，受环境因素修饰，已被证明在生物标志物中有价值 发现了许多慢性疾病。根据我们的初步数据，前列腺素合成的上调 可能是青春期子宫内膜异位症病理生理学的重要途径， 带着痛苦使用详细的临床信息，疼痛测量，加上配对的血液和腹腔液样本 从妇女健康研究的纵向队列中：从青春期到成年 队列，我们将应用一个经过验证的代谢组学平台，可以同时测量600多个 代谢物，使我们能够确定代谢物和生物学途径独特的青春期子宫内膜异位症。的 提出的目标将确定新的代谢生物标志物的青少年子宫内膜异位症，这可能导致 子宫内膜异位症的早期诊断生物标志物和个性化治疗策略的研究进展 重要的是，阐明青少年子宫内膜异位症的分子特征将提供关于子宫内膜异位症的新信息。 在疾病轨迹的早期过程中的病理生理学，为未来的R01提案提供信息，以阐明 随着疾病从青春期向成年期进展，代谢组学特征发生变化。

ABSTRACT Endometriosis is a debilitating disease affecting 200 million women worldwide, causing severe pain and infertility. Although over 50% of adults with endometriosis report onset of pain during adolescence, most women with endometriosis experience a delayed diagnosis on average of seven years due to the current diagnostic standard of surgical visualization, resulting in prolonged pain and decreased quality of life. Thus, there is a critical need to identify novel, non-invasive biomarkers for endometriosis, which is one of the NICHD research goals related to endometriosis. Being able to diagnose endometriosis earlier in the life course, during adolescence and young adulthood, may lead to earlier intervention and improved clinical outcome. However, little is known about the pathophysiology and molecular features of endometriosis diagnosed in adolescents. Adolescent endometriosis typically presents with severe pelvic pain and superficial peritoneal lesions, which is distinct from adult-diagnosed endometriosis which typically present with pain, infertility, and deep fibrotic lesions. Furthermore, our preliminary data shows that about 30% of adolescents with endometriosis suffer from persistent or recurring post-surgical pelvic pain despite being treated with post-surgical hormone therapy, leading to recurring surgeries. Recently, we reported that blood CA125, which is elevated in endometriosis diagnosed in adults, was not elevated in adolescents with endometriosis. Adolescent-diagnosed endometriosis may have distinct molecular phenotype compared to adult-diagnosed endometriosis, which may require different strategies for diagnosis and treatment. The objective of this application is to identify novel (1) blood metabolomic profiles associated with adolescent endometriosis and (2) peritoneal fluid metabolomic markers predictive of persistent post-surgical pain. Metabolites are the downstream products of cellular activities regulated by the genome and modified by environmental factors and have proven valuable in biomarker discovery for many chronic diseases. Based on our preliminary data, upregulation of prostaglandin synthesis could be an important pathway for adolescent endometriosis pathophysiology given its common presentation with pain. Using the detailed clinical information, pain measures, plus paired blood and peritoneal fluid samples from the well-annotated longitudinal cohort of the Women’s Health Study: From Adolescence to Adulthood cohort, we will apply a validated metabolomics platform which can simultaneously measure over 600 metabolites, allowing us identify metabolites and biologic pathways unique to adolescent endometriosis. The proposed aims will identify novel metabolomic biomarkers of adolescent endometriosis which may lead to advances in determining early diagnostic biomarkers and personalized treatment strategies for endometriosis. Importantly, elucidating molecular profiles of adolescent endometriosis will provide new information about the pathophysiology during the earlier course the disease trajectory, informing future R01 proposals to elucidate changes in metabolomic profiles as the disease progresses from adolescence to adulthood.