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

• 批准号: 10474470
• 负责人: STEVEN L YOUNG
• 金额: $ 140.53万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474470
• 关键词: Affect; Animal Model; Awareness; Bioinformatics; Cell Proliferation; Chronic; Clinical; Clinical Research; Collaborations; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Disease; Dysmenorrhea; Early Diagnosis; Early treatment; Education and Outreach; Endometrial; Energy Metabolism; Engineering; Epigenetic Process; Epithelial; Estrogen Receptors; Evaluation; Functional disorder; Future; Genomics; Goals; Growth; HDAC4 gene; Health; Health Benefit; Heart; Human; Image; Imaging Techniques; In Vitro; Infertility; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Knowledge; Lesion; Macaca mulatta; Metabolic; Methods; Modeling; Molecular; Molecular Target; Monkeys; Mus; Operative Surgical Procedures; Pain; Patients; Personal Satisfaction; Plant Roots; Play; Post-Translational Protein Processing; Process; Progesterone; Progesterone Receptors; Proteins; Provider; Research Personnel; Resistance; Resolution; Role; SIRT1 gene; Scientist; Signal Transduction; Stigmatization; System; Testing; Testosterone; Therapeutic; Tissues; Uterus; Woman; base; care providers; chronic pelvic pain; college; community setting; comparative; comparative genomics; design; endometriosis; high school; human data; imaging modality; implantation; improved; in vitro Model; innovation; insight; lipid mediator; non-invasive imaging; nonhuman primate; noninvasive diagnosis; novel; overexpression; pre-clinical; prevent; protein function; receptor expression; synergism; therapeutic target; tool; western diet; young woman

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.

合作中心开发改进的子宫内膜异位症诊断和治疗方法 抽象的 该中心的总体目标是开发先进的工具和见解以增进理解 子宫内膜异位症的病理生理学，子宫内膜组织生长在子宫外的疾病 会引起严重的痛经、疼痛、不孕等后遗症。我们追求这一目标是为了增强 诊断、评估和治疗患有这种常见且毁灭性疾病的妇女。一个清晰的 对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 手术进行诊断和病变评估。对手术的依赖会延误诊断并防止频繁或 反复评价。然而，近年来，我们团队中科学家之间的合作取得了进展 统一的病理生理学原理——黄体酮抵抗。大多数其他病理生理学特征 子宫内膜异位症，包括持续性上皮雌激素受体作用、持续性雌激素受体和 黄体酮受体表达、细胞增殖、炎症、疼痛和不孕症可归因于 黄体酮抵抗。最近，该联盟的重要发现表明，Sirtuin 1 (SIRT1) 表观遗传调节剂，可引起黄体酮抵抗，导致下游效应加剧。 SIRT1 是一种组蛋白脱乙酰酶，也直接调节指导炎症和炎症的蛋白质的功能。 代谢信号。我们发现子宫内膜 SIRT1 在我们拥有的所有物种中一致过度表达 测试对象包括人类、非人类灵长类动物和小鼠，这凸显了 SIRT1 在 子宫内膜异位症病理生理学。此外，初步研究表明 SIRT1 过度表达起着 对病变存活和不孕症有直接作用，并具有作为治疗靶点的潜在作用。我们呈现三 基于我们迅速发展的病理生理学数据的关键项目，以加深我们的知识，促进 开发新型非侵入性诊断和评估方法并推广非激素治疗 受影响妇女的选择。这三个项目对女性的影响将通过患者和 子宫内膜异位症外展和教育 (EOE) 核心和深度整合的提供者教育举措 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。总的来说，这些项目和核心有助于三个协同作用 目标：1）通过开发非侵入性技术来加强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 疾病过程的基础； 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持久的改进 在患有子宫内膜异位症的女性的生活中。