Risk factors for early pregnancy loss

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 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.