The role of ARID1A in endometriosis-related infertility

ARID1A 在子宫内膜异位症相关不孕症中的作用

• 批准号: 10216183
• 负责人: Ryan Marquardt
• 金额: $ 3.04万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-16 至 2022-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216183
• 关键词: ARID1A gene; Address; Affect; Characteristics; Chromatin Remodeling Factor; Complex; Decidual Cell Reactions; Defect; Development; Diagnosis; Disease; Early Diagnosis; Emotional; Endometrial; Endometrium; Environment; Epithelial; Estrogens; Fertility; Functional disorder; Genes; Genetic Transcription; Infertility; Knockout Mice; LIF gene; Lesion; Link; Medical; Medical Care Costs; Molecular; Morphology; Mus; Nucleosomes; Ovarian; Pain; Pathway interactions; Pregnancy Maintenance; Progesterone; Progesterone Receptors; Proteins; Regulation; Research; Resistance; Role; STAT3 gene; Sampling; Signal Pathway; Signal Transduction; Specificity; System; Testing; Tissue Sample; Tissues; United States; Uterine cavity; Uterus; Woman; aged; base; child bearing; early detection biomarkers; early pregnancy loss; endometriosis; endometriosis-related infertility; eutopic endometrium; experience; hormonal signals; implantation; improved outcome; innovation; mouse model; natural Blastocyst Implantation; protein complex; reproductive; steroid hormone; tool; uterine receptivity

ABSTRACT Endometriosis occurs when endometrial tissue grows outside the uterine cavity, and this painful disease afflicts about 10% of reproductive-aged women. Up to 50% of these women also experience infertility, and many cases cannot be explained by morphological or ovarian defects, which implicates a uterine environment non- receptive to embryo implantation. The molecular basis for the correlation of endometriosis and uterine non- receptivity is unclear, but it likely involves signaling downstream of the steroid hormones progesterone and estrogen in the endometrium. Progesterone and estrogen signaling must be tightly regulated for the successful establishment and maintenance of pregnancy but they imbalanced in endometriosis, leading to progesterone resistance and estrogen dominance. ARID1A, a chromatin remodeling factor, is directly associated with progesterone signaling through the progesterone receptor and is remarkably reduced in the endometrium of infertile women with endometriosis. ARID1A is necessary for fertility in mice due to its role supporting implantation, decidualization, and endometrial receptivity. Uterine loss of ARID1A results in aberrant epithelial proliferation characteristic of progesterone resistance in women with endometriosis. We hypothesize that ARID1A loss provides the molecular key to endometriosis-related infertility by causing increased endometriotic lesion development and decreased endometrial receptivity based on its role regulating steroid hormone signaling. We will address the complex problem of endometriosis-related infertility by examining the causal link between ARID1A loss in endometriotic lesions and the development of endometriosis-related infertility (Aim 1) as well as the endometrial compartment-specific role of ARID1A loss in the dysregulation of steroid hormone signaling observed in the eutopic endometrium of women endometriosis (Aim 2). Our innovative endometriosis model mice, uterine Arid1a knockout mice, and tissue samples from infertile women with endometriosis will be powerful tools to analyze ARID1A's role in the pathophysiology of endometriosis-related infertility and the dysregulated molecular mechanisms of steroid hormone signaling in the endometriosis-affected uterus.

摘要 子宫内膜异位症是指子宫内膜组织在宫腔外生长，这是一种痛苦的疾病。 约10%的育龄妇女。这些妇女中高达50%的人还经历过不孕不育，而且许多 这些病例不能用形态或卵巢缺陷来解释，这意味着子宫环境不正常 能接受胚胎植入的。子宫内膜异位症与子宫非癌相关性的分子基础 感受性尚不清楚，但它可能涉及类固醇荷尔蒙黄体酮和黄体酮下游的信号传递。 子宫内膜中的雌激素。孕激素和雌激素信号必须受到严格调控才能成功 妊娠的建立和维持，但它们在子宫内膜异位症中失衡，导致孕酮 耐药性和雌激素优势。ARID1a是一种染色质重塑因子，直接与 孕酮信号通过孕酮受体，在子宫内膜中显著减少。 患有子宫内膜异位症的不孕妇女。ARID1A是小鼠生育所必需的，因为它的作用是支持 着床、蜕膜形成和子宫内膜容受性。子宫ARID1A基因缺失导致上皮细胞异常 子宫内膜异位症患者孕酮抵抗的增殖特点。我们假设 ARID1a缺失是子宫内膜异位症相关不孕症的分子关键，它导致子宫内膜异位症的增加 基于其调节类固醇激素作用的病变发展和子宫内膜容受性降低 发信号。我们将通过研究因果联系来解决子宫内膜异位症相关不孕症的复杂问题。 子宫内膜异位症病变中ARID1a缺失与子宫内膜异位症相关性不孕症的发生(目标1) 以及ARID1A缺失在类固醇激素失调中的子宫内膜室特异性作用 子宫内膜异位症在位内膜内信号的观察(目标2)。我们创新的子宫内膜异位症 模型小鼠、子宫ARID1A基因敲除小鼠和患有子宫内膜异位症的不孕妇女的组织样本将被 分析ARID1A在子宫内膜异位症相关不孕症的病理生理学中的作用的有力工具 子宫内膜异位症子宫中类固醇激素信号的分子机制失调。

项目成果

Endometrial epithelial ARID1A is critical for uterine gland function in early pregnancy establishment.

• DOI: 10.1096/fj.202002178r
• 发表时间: 2021-03
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Marquardt RM;Kim TH;Yoo JY;Teasley HE;Fazleabas AT;Young SL;Lessey BA;Arora R;Jeong JW
• 通讯作者: Jeong JW