Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis

开发子宫内膜异位症诊断和治疗方法的合作中心 摘要 该中心的首要目标是开发先进的工具和见解，以提高认识 子宫内膜异位症是一种子宫内膜组织在子宫外生长的疾病， 严重时可引起痛经、疼痛、不孕等后遗症。我们追求这一目标， 诊断，评估和治疗患有这种常见和毁灭性疾病的妇女。一个明确 子宫内膜异位症的病理生理学理解一直难以实现，部分原因是依赖于 手术诊断和病变评估。对手术的依赖会延误诊断， 反复评价。然而，近年来，我们团队中科学家之间的合作已经推进了一个新的领域。 统一的病理生理学原理--孕酮抵抗。大多数其他病理生理特征 子宫内膜异位症，包括持续性上皮雌激素受体作用，持续性雌激素受体和 孕激素受体表达、细胞增殖、炎症、疼痛和不育，可归因于 孕酮抵抗最近，该财团的重要发现表明，Sirtuin 1（SIRT 1）， 表观遗传调节剂，可引起孕激素抵抗，导致下游效应加剧。 SIRT 1是一种组蛋白脱乙酰酶，也直接调节引导炎症和炎症反应的蛋白质的功能。 代谢信号我们发现，在我们所研究的所有物种中， 包括人类，非人类灵长类动物和小鼠，强调了SIRT 1可能在 子宫内膜异位症的病理生理学此外，初步研究表明，SIRT 1过表达在细胞凋亡中起作用。 直接作用于病变存活以及不孕症，并具有作为治疗靶点的潜在作用。我们提出了三 基于我们新兴的病理生理学数据的关键项目，以加深我们的知识，催化 开发新的非侵入性诊断和评估方法，并促进非激素治疗 受影响妇女的选择。这三个项目对妇女的影响将通过耐心和 提供来自子宫内膜异位症外展和教育（EOE）核心和深度整合的教育举措 来自人、非人灵长类动物、小鼠和体外系统的协同数据，由比较方案增强。 Genomics and Bioinformatics（CGB）Core.总体而言，这些项目和核心有助于实现三个协同效应， 目的：1）通过建立无创性的子宫内膜异位症诊断方法，提高对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 3）开发新的非激素、非手术治疗的分子靶点， 子宫内膜异位症的治疗;这些目标的成功完成将导致长期的改善 子宫内膜异位症患者的生活。

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.