Role of chromatin remodeling and cell signaling in endometriosis etiology

染色质重塑和细胞信号传导在子宫内膜异位症病因学中的作用

• 批准号: 10004701
• 负责人: Ronald L Chandler
• 金额: $ 19.56万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004701
• 关键词: ATP Hydrolysis; Abdominal Cavity; Address; Affect; Age; Binding Sites; Biochemical; Biology; Catalytic Domain; Cell Polarity; Cell-Cell Adhesion; Characteristics; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Complex; Disease; Endometrial; Endometrium; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Estrogens; Etiology; Frequencies; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genomics; Greater sac of peritoneum; Growth; Homeostasis; Human; Immune; Infertility; Inflammation; Inflammatory; Lead; Lesion; Mesenchymal; Molecular; Molecular Conformation; Mutation; Nucleosomes; Oncogenic; Outcome; PIK3CA gene; Pain; Pathway interactions; Peritoneal; Phase II Clinical Trials; Phenotype; Phosphatidylinositols; Phosphotransferases; Physiological; Proteins; Regulator Genes; Repression; Retrograde Menstruation; Rheumatoid Arthritis; Role; SWI/SNF Family Complex; Signal Pathway; Signal Transduction; Site; Somatic Mutation; Therapeutic; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Up-Regulation; Woman; chromatin remodeling; endometriosis; exome sequencing; experimental study; genome-wide; immunoreactivity; inhibitor/antagonist; insight; jun Oncogene; metastatic process; mouse model; mutant; prevent; programs; promoter; reproductive; theories; transcription factor; transcriptome

Project Summary Endometriosis affects 10-15% of women of reproductive age and is a leading cause of pain and infertility. Endometriosis is commonly associated with inflammation and the estrogen dependent, non-neoplastic spread of endometrial tissue to the peritoneal cavity. While current theories on the causes of endometriosis support a role for physiological dysfunction in the endometrium (i.e. retrograde menstruation), the genetic and molecular mechanisms underlying the etiology of the disease are poorly understood. Recent exome sequencing of endometriotic lesions identified mutations in proteins involved in chromatin remodeling and cell signaling. We hypothesize that mutations in chromatin remodeling and cell signaling pathways activate transcriptional programs required for cellular dissemination and invasion, leading to the estrogen-dependent spread of endometrial tissue. In Aim 1, we will utilize genetic and genome-wide sequencing approaches to determine the mechanism by which chromatin remodeling regulates normal endometrial epithelial cell identity and homeostasis. In Aim 2, we will use a newly developed mouse model of endometriosis that mimics the natural spread of endometriotic tissue to address the role of the Activator Protein-1 (AP-1) signaling transcription factor complex in invasion. This proposal will provide insight into the molecular mechanisms that promote the initial establishment and spread of endometriosis.

项目摘要 子宫内膜异位症影响10-15%的育龄妇女，是疼痛和不孕的主要原因。 子宫内膜异位症通常与炎症和雌激素依赖的非肿瘤性扩散有关 子宫内膜组织转移到腹腔虽然目前关于子宫内膜异位症病因的理论支持 生理功能障碍在子宫内膜中的作用（即逆行月经），遗传和分子 对该疾病的病因学机制知之甚少。最近的外显子组测序 肿瘤病变鉴定了参与染色质重塑和细胞信号传导的蛋白质的突变。我们 假设染色质重塑和细胞信号传导途径中的突变激活转录因子， 细胞传播和入侵所需的程序，导致雌激素依赖性的传播， 子宫内膜组织在目标1中，我们将利用遗传和全基因组测序方法来确定 染色质重塑调节正常子宫内膜上皮细胞身份的机制， 体内平衡。在目标2中，我们将使用一种新开发的子宫内膜异位症小鼠模型， 肿瘤组织的扩散以解决激活蛋白-1（AP-1）信号传导转录因子的作用 复杂的入侵。这项建议将提供深入了解的分子机制，促进最初的 子宫内膜异位症的建立和扩散。