Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis

合作中心开发改进的子宫内膜异位症诊断和治疗方法 摘要 该中心的首要目标是开发先进的工具和洞察力，以提高理解 子宫内膜异位症是一种子宫内膜组织生长在子宫外的疾病， 可引起严重痛经、疼痛、不孕等后遗症。我们追求这一目标是为了加强 诊断、评估和治疗患有这种常见和破坏性疾病的妇女。一目了然 对子宫内膜异位症的病理生理学理解一直很难实现，部分原因是依赖于 诊断和病变评估的外科手术。依赖手术会延误诊断，并防止频繁或 反复评估。然而，近年来，我们团队中的科学家之间的合作推动了 统一病理生理学原理--黄体酮抵抗原理。大多数其他病理生理学特征 子宫内膜异位症，包括持续性上皮性雌激素受体作用，持续性雌激素受体和 孕激素受体的表达、细胞增殖、炎症、疼痛和不孕可归因于 黄体酮抵抗。最近，该联盟的重要发现表明，Sirtuin 1(SIRT1)，一种 表观遗传调节剂，可引起孕酮耐药，导致下游效应加重。 SIRT1是一种组蛋白脱乙酰酶，它还直接调节蛋白质的功能，引导炎症和 代谢信号。我们发现子宫内膜SIRT1在我们所有的物种中持续过表达 经过测试，包括人类、非人类灵长类动物和小鼠，突显了SIRT1在 子宫内膜异位症病理生理学。此外，初步研究表明，SIRT1的过度表达对 在病变存活和不孕不育方面发挥直接作用，并具有潜在的治疗靶点作用。我们为您呈现三个 基于我们迅速增长的病理生理数据的关键项目，以加深我们的知识，催化 开发新的、非侵入性的诊断和评估方法，促进非激素治疗 为受影响的女性提供选择。这三个项目对妇女的影响将通过耐心和 来自子宫内膜异位症外展和教育(EOE)核心和深度融合的提供者教育倡议 来自人类、非人类灵长类动物、小鼠和体外系统的协同数据，通过比较增强 基因组学和生物信息学(CGB)核心。总体而言，项目和核心有助于三个协同作用 目的：1)通过发展非侵入性技术提高子宫内膜异位症病变的早期诊断和评估 成像技术和提高公众意识；2)确定炎症和代谢变化 这是疾病过程的基础；以及3)开发非激素、非手术的新分子靶点。 子宫内膜异位症的治疗；成功完成这些目标将带来长期的改善 在患有子宫内膜异位症的妇女的生活中。

Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis ABSTRACT The overarching goal of this Center is to develop advanced tools and insights for improved understanding of the pathophysiology of endometriosis, a disease in which endometrial tissue grows outside the uterus and can cause severe dysmenorrhea, pain, infertility and other sequelae. We pursue this goal to enhance the diagnosis, assessment, and treatment of women suffering from this common and devastating disease. A clear pathophysiologic understanding of endometriosis has been difficult to achieve due, in part, to the reliance on surgery for diagnosis and lesion assessment. Reliance on surgery delays diagnosis and prevents frequent or repeated evaluation. In recent years, however, collaborations between scientists in our team have advanced a unifying pathophysiological principle--that of progesterone resistance. Most other pathophysiological features of endometriosis, including persistent epithelial estrogen receptor action, persistent estrogen receptor and progesterone receptor expression, cellular proliferation, inflammation, pain, and infertility, can be ascribed to progesterone resistance. Recently, important findings by this consortium show that Sirtuin 1 (SIRT1), an epigenetic modulator, can cause progesterone resistance, resulting in exacerbation of downstream effects. SIRT1 is a histone deacetylase that also directly regulates the function of proteins directing inflammatory and metabolic signaling. We find consistent overexpression of endometrial SIRT1 across all species that we have tested, including humans, non-human primates, and mice, highlighting a likely central role for SIRT1 in endometriosis pathophysiology. Furthermore, preliminary studies indicate that SIRT1 overexpression plays a direct role in lesion survival as well as infertility and has a potential role as a therapeutic target. We present three key projects based on our burgeoning pathophysiological data to deepen our knowledge, catalyze the development of novel, non-invasive diagnostic and assessment methods and promote non-hormonal therapeutic options for affected women. The impact of these three projects on women will be enhanced by patient and provider educational initiatives from the Endometriosis Outreach and Education (EOE) Core and deep integration of synergistic data from human, non-human primate, mouse, and in vitro systems, enhanced by the Comparative Genomics and Bioinformatics (CGB) Core. Collectively, the projects and cores contribute to three synergistic aims: 1) Enhance early diagnosis and assessment of endometriosis lesions by developing non-invasive imaging techniques and promoting public awareness; 2) Determine inflammatory and metabolic changes that underlie the disease process; and 3) Develop new molecular targets for non-hormonal, non-surgical treatments for endometriosis; The successful completion of these aims will lead to a long-lasting improvement in the lives of women suffering from endometriosis.