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: 10662485
• 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/10662485
• 关键词: ARID1A gene; ATP Hydrolysis; Acetylation; Affect; Age; Anoikis; Biochemical; Biological Availability; Biological Models; Bromodomain; Bromodomains and extra-terminal domain inhibitor; Cell Death; Cells; Chromatin; Chromatin Remodeling Factor; Complex; Development; Diagnosis; Disease; EP300 gene; Endometrial; Enhancers; Epigenetic Process; Epithelial Cells; Epithelium; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Genome; Genome Mappings; Genomic approach; Genomics; Goals; Greater sac of peritoneum; Growth; Histone Acetylation; Histone H2A; Histone H4; Histones; Infertility; Invaded; Lesion; Lysine; Mesenchymal; Molecular; Mutation; Nucleosomes; Operative Surgical Procedures; Oral; Outcome; PIK3CG gene; Pain management; Pathway interactions; Patients; Phase I/II Clinical Trial; Phenotype; Prevention; Prevention strategy; Recurrence; Repression; Research; Retrograde Menstruation; Role; Site; Somatic Mutation; Sorting; 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; 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.

项目摘要 子宫内膜异位症影响十分之一的生殖年龄女性，与慢性骨盆疼痛和 不育。该疾病的特征是在外部的部位存在异常子宫内膜组织 子宫。当前的子宫内膜异位症治疗选择仅限于手术，激素治疗和疼痛 管理。非荷尔蒙治疗方案的需求未满足，专门针对异常 子宫内膜组织。逆行月经促进了子宫内膜组织从子宫传播到 腹膜腔内的异位部位。尽管逆行月经在建立中起作用 该疾病是子宫内膜异位发育所需的其他因素。了解流离失所 子宫内膜细胞引起疾病需要了解允许的分子机制 子宫内膜细胞侵入，生存和定居异位部位。最近的复发ARID1A的鉴定 子宫内膜损伤中的突变支持子宫内膜异位中表观遗传失调的因果作用 发展。我们假设表观遗传失调使子宫内膜细胞偏向于 子宫内膜异位症通过促进基因和子宫内膜细胞所必需的途径的异常表达 入侵和生存。在这项研究中，我们将利用创新的模型系统和高级``Omics Technologies'' 研究基因组，表观基因组和转录组在子宫内膜异位发展中的作用，并告知 新的预防和治疗策略。在AIM 1中，我们将确定组蛋白的机制 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用的理由是女性的潜在非荷尔蒙治疗策略 与子宫内膜异位症。在AIM 2中，我们将解决变异组蛋白交换在子宫内膜异位症中的作用 发展。我们的主要目标是发现导致的表观遗传调节机制 子宫内膜异位症，并通过利用利用 疾病的表观遗传改变引起的脆弱性。我们的理想目标是确定新的 明确诊断，预防和治疗子宫内膜异位症的方法。

项目成果

AP-1 Subunit JUNB Promotes Invasive Phenotypes in Endometriosis.

• DOI: 10.1007/s43032-022-00974-3
• 发表时间: 2022-11
• 期刊: Reproductive sciences (Thousand Oaks, Calif.)

ARID1A-dependent maintenance of H3.3 is required for repressive CHD4-ZMYND8 chromatin interactions at super-enhancers.

• DOI: 10.1186/s12915-022-01407-y
• 发表时间: 2022-09-25
• 期刊: BMC BIOLOGY
• 影响因子: 5.4
• 作者: Reske, Jake J.;Wilson, Mike R.;Armistead, Brooke;Harkins, Shannon;Perez, Cristina;Hrit, Joel;Adams, Marie;Rothbart, Scott B.;Missmer, Stacey A.;Fazleabas, Asgerally T.;Chandler, Ronald L.
• 通讯作者: Chandler, Ronald L.

SWI/SNF Antagonism of PRC2 Mediates Estrogen-Induced Progesterone Receptor Expression.

• DOI: 10.3390/cells11061000
• 发表时间: 2022-03-15
• 期刊: Cells
• 影响因子: 6
• 作者: Wilson MR;Reske JJ;Koeman J;Adams M;Joshi NR;Fazleabas AT;Chandler RL
• 通讯作者: Chandler RL

Transcriptome and DNA methylome analyses reveal underlying mechanisms for the racial disparity in uterine fibroids.

• DOI: 10.1172/jci.insight.160274
• 发表时间: 2022-10-24
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Paul, Emmanuel N.;Grey, Joshua A.;Carpenter, Tyler J.;Madaj, Zachary B.;Lau, Kin H.;Givan, Scott A.;Burns, Gregory W.;Chandler, Ronald L.;Wegienka, Ganesa R.;Shen, Hui;Teixeira, Jose M.
• 通讯作者: Teixeira, Jose M.

PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin.

• DOI: 10.1186/s12958-023-01094-6
• 发表时间: 2023-05-11
• 期刊: Reproductive biology and endocrinology : RB&E