Epigenetic regulatory mechanisms and therapeutic opportunities in endometriosis

项目摘要 每10名育龄妇女中就有1名患有子宫内膜异位症，并伴有慢性盆腔疼痛， 不孕该疾病的特征是在子宫内膜外的部位存在异常的子宫内膜组织。 子宫目前子宫内膜异位症的治疗选择仅限于手术，激素治疗和疼痛 管理有一个未满足的需要，非激素治疗方案，专门针对异常 子宫内膜组织逆行性月经促进子宫内膜组织从子宫扩散到 腹膜腔内的异位部位。虽然逆行月经在建立 子宫内膜异位症的发生和发展，需要更多的因素。了解如何流离失所 子宫内膜细胞引起的疾病需要了解的分子机制， 子宫内膜细胞侵入、存活并定植在异位部位。复发性ARID1A的最新鉴定 子宫内膜异位症病变中的突变支持表观遗传失调在子宫内膜异位症中的因果作用 发展我们假设表观遗传失调使移位的子宫内膜细胞倾向于 子宫内膜异位症通过促进子宫内膜细胞所必需的基因和途径的异常表达 入侵与生存在这项研究中，我们将利用创新的模型系统和先进的`组学技术 研究基因组、表观基因组和转录组在子宫内膜异位症发展中的作用， 新的预防和治疗策略。在目标1中，我们将确定组蛋白 乙酰转移酶活性和组蛋白乙酰化促进子宫内膜侵袭和存活。我们将提供 组蛋白乙酰转移酶抑制作为女性潜在非激素治疗策略的基本原理 子宫内膜异位症在目标2中，我们将讨论组蛋白交换变异在子宫内膜异位症中的作用 发展我们的主要目标是揭示表观遗传调控机制，导致 子宫内膜异位症，并找到新的方法来治疗靶向异常子宫内膜细胞， 这种疾病的表观遗传变异导致的脆弱性。我们的理想目标是确定新的 子宫内膜异位症的预防和治疗

Project Summary Endometriosis affects 1 in 10 women of reproductive age and is associated with chronic pelvic pain and infertility. The disease is characterized by the presence of abnormal endometrial tissue at sites outside the uterus. Current treatment options for endometriosis are limited to surgery, hormone therapy and pain management. There is an unmet need for non-hormonal treatment options that specifically target abnormal endometrial tissue. Retrograde menstruation promotes the spread of endometrial tissue from the uterus to ectopic sites within the peritoneal cavity. Although retrograde menstruation plays a role in the establishment of the disease, additional factors are necessary for endometriosis development. Understanding how displaced endometrial cells cause the disease requires an understanding of the molecular mechanisms that allow endometrial cells to invade, survive and colonize ectopic sites. The recent identification of recurrent ARID1A mutations in endometriotic lesions supports a causal role for epigenetic dysregulation in endometriosis development. We hypothesize that epigenetic dysregulation predisposes displaced endometrial cells to endometriosis by promoting the aberrant expression of genes and pathways necessary for endometrial cell invasion and survival. In this study, we will utilize innovative model systems and advanced `omics technologies to investigate the role of the genome, epigenome and transcriptome in endometriosis development and inform new prevention and treatment strategies. In Aim 1, we will determine the mechanism by which histone acetyltransferase activity and histone acetylation promotes endometrial invasion and survival. We will provide rationale for histone acetyltransferase inhibition as a potential non-hormonal therapeutic strategy for women with endometriosis. In Aim 2, we will address the role of variant histone exchange in endometriosis development. Our primary objectives are to uncover the epigenetic regulatory mechanisms that lead to endometriosis and find new ways to therapeutically target abnormal endometrial cells by leveraging vulnerabilities that arise from epigenetic alterations in the disease. Our aspirational goals are to identify new ways to definitively diagnose, prevent and treat endometriosis.