Epigenetic regulatory mechanisms and therapeutic opportunities in endometriosis

子宫内膜异位症的表观遗传调控机制和治疗机会

• 批准号: 10295909
• 负责人: Ronald L Chandler
• 金额: $ 33.65万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295909
• 关键词: ARID1A gene; ATP Hydrolysis; Acetylation; Address; Affect; Age; Anoikis; Biochemical; Biological Availability; Biological Models; Bromodomain; Cell Death; Cells; Chromatin; Chromatin Remodeling Factor; Complex; Development; Diagnosis; Disease; EP300 gene; Endometrial; Enhancers; Epigenetic Process; Epithelial; Epithelial Cells; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Genome; Genomic approach; Genomics; Goals; Greater sac of peritoneum; Growth; Histone Acetylation; Histone H2A; Histone H4; Histones; Infertility; Invaded; Lead; Lesion; Lysine; Maps; Mesenchymal; Molecular; Mutation; Nucleosomes; Operative Surgical Procedures; Oral; Outcome; Pain management; Pathway interactions; Patients; Phase I/II Clinical Trial; Phenotype; Play; Prevention; Prevention strategy; Recurrence; Research; Retrograde Menstruation; Role; Site; Somatic Mutation; Technology; Therapeutic; Tissues; Toxic effect; Uterus; Variant; Woman; Women' s Health; Work; chromatin remodeling; chronic pelvic pain; endometriosis; epigenetic drug; epigenome; experimental study; genome-wide; histone acetyltransferase; hormone therapy; immunoreactivity; in vivo; inhibitor/antagonist; innovation; mouse model; mutant; prevent; reproductive; theories; therapeutic target; transcriptome; treatment strategy

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.

项目概要 子宫内膜异位症影响十分之一的育龄妇女，并与慢性盆腔疼痛和 不孕症。该疾病的特征是在子宫外部位存在异常子宫内膜组织。 子宫。目前子宫内膜异位症的治疗选择仅限于手术、激素治疗和疼痛治疗 管理。对专门针对异常的非激素治疗方案的需求尚未得到满足 子宫内膜组织。月经逆行促进子宫内膜组织从子宫扩散到子宫 腹膜腔内的异位部位。虽然逆行月经在建立 在这种疾病中，子宫内膜异位症的发展需要其他因素。了解如何流离失所 子宫内膜细胞导致该疾病需要了解其分子机制 子宫内膜细胞侵入、存活并定植异位。复发性 ARID1A 的最新鉴定 子宫内膜异位病变的突变支持子宫内膜异位症表观遗传失调的因果作用 发展。我们假设表观遗传失调导致子宫内膜细胞移位 通过促进子宫内膜细胞必需的基因和途径的异常表达来治疗子宫内膜异位症 入侵和生存。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并提供信息 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 患有子宫内膜异位症。在目标 2 中，我们将探讨变异组蛋白交换在子宫内膜异位症中的作用 发展。我们的主要目标是揭示导致的表观遗传调控机制 子宫内膜异位症，并通过利用来寻找治疗靶向异常子宫内膜细胞的新方法 由于疾病的表观遗传改变而产生的脆弱性。我们的理想目标是发现新的 明确诊断、预防和治疗子宫内膜异位症的方法。