Risk factors for early pregnancy loss

 描述(申请人提供)：根据疾控中心的数据，15-44岁的已婚妇女中有6%不育，12.1%的妇女在怀孕或怀孕到足月时表现出困难。20周前的妊娠丢失称为早孕丢失或流产。在已知的怀孕中，约有15%会发生这种情况。植入缺陷导致了75%以上的失败妊娠，这表明需要将研究重点放在了解子宫容受性和成功植入所必需的复杂机制上。富含AT相互作用结构域的蛋白1A(ARID1A)是SWI/SNF家族的一员，在转录水平上激活通常被染色质抑制的基因是必需的。ARID1a缺失是子宫内膜癌和子宫内膜异位症相关卵巢癌的常见事件。然而，对ARID1A突变的病理生理效应的了解仍然很少，而且ARID1A在女性生殖轨道中的功能仍然难以捉摸。在我们的研究中，ARID1A丢失与子宫内膜异位症不孕妇女有关。此外，子宫特异性ARID1A基因敲除小鼠由于着床和蜕膜缺陷而不育。在突变小鼠的围着床期，E2信号和上皮细胞的增殖显著增加。在突变小鼠中，上皮PGR及其靶基因的水平下调。在这些数据的基础上，我们推测ARID1A通过抑制ESR1活性和增强PGR活性在着床和蜕膜形成过程中发挥重要作用。一种创新的治疗策略将是利用小鼠动物模型和人类子宫内膜异位症样本进行临床前研究，旨在阻止异常的上皮细胞增殖，并克服不孕症患者蜕膜受损的问题。

 DESCRIPTION (provided by applicant): According to the CDC, 6% of married women between the ages of 15-44 are infertile, and 12.1% of women display difficulties getting pregnant or carrying a pregnancy to term. The loss of pregnancy before 20 weeks is called early pregnancy loss or miscarriage. They occur in about 15% of known pregnancies. Implantation defects contribute to over 75% of failed pregnancies, suggesting a need to focus research efforts towards understanding the complex mechanisms necessary for uterine receptivity and successful implantation. AT-rich interactive domain-containing protein 1A (ARID1A) is a member of the SWI/SNF family and is required for transcriptional activation of genes normally repressed by chromatin. ARID1A loss is a frequent event in endometrial cancers and endometriosis-associated ovarian carcinomas. However, an understanding of the pathophysiological effects of ARID1A mutations remains quite poor and the function of ARID1A in the female reproductive track has remained elusive. In our studies, ARID1A loss is implicated in infertile women with endometriosis. Furthermore, uterine-specific Arid1a knock-out mice were sterile due to a defect of implantation and decidualization. E2 signaling and proliferation of epithelium were significantly increased at the peri-implantation period of the mutant mice. The levels of epithelial PGR and its target genes are downregulated in mutant mice. On the basis of all these data, we hypothesized that ARID1A plays an important role for implantation and decidualization by suppressing ESR1 activities and enhancing PGR activities. An innovative therapeutic strategy would be to conduct preclinical studies designed to block aberrant epithelial proliferation and overcome impaired decidualization in infertility using mouse animal models as well as human endometriosis samples.