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.

Public Health Relevance

Miscarriage before 20 weeks occurs in about 15% of known pregnancies, and over 75% of failed pregnancies involve implantation defects. However, relatively little is known about the molecular mechanisms and the precise etiology of infertility. Therefore, we propose to develop and validate a therapeutic strategy designed to block estrogen signaling in infertility using mouse models as well as human endometriosis samples.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD084478-02
Application #
9257438
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Yoshinaga, Koji
Project Start
2016-04-10
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$289,462
Indirect Cost
$102,712
Name
Michigan State University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Teasley, Hanna E; Chang, Hye Jin; Kim, Tae Hoon et al. (2018) Expression of PIK3IP1 in the murine uterus during early pregnancy. Biochem Biophys Res Commun 495:2553-2558
Yoo, J-Y; Yang, W S; Lee, J H et al. (2018) MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells. Oncogene 37:255-262
Chang, Hye Jin; Yoo, Jung-Yoon; Kim, Tae Hoon et al. (2018) Overexpression of Four Joint Box-1 Protein (FJX1) in Eutopic Endometrium From Women With Endometriosis. Reprod Sci 25:207-213
Yoo, Jung-Yoon; Kim, Tae Hoon; Fazleabas, Asgerally T et al. (2017) KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance. Sci Rep 7:6765
Yoo, Jung-Yoon; Ahn, Jong Il; Kim, Tae Hoon et al. (2017) G-protein coupled receptor 64 is required for decidualization of endometrial stromal cells. Sci Rep 7:5021
Fox, Chelsea; Morin, Scott; Jeong, Jae-Wook et al. (2016) Local and systemic factors and implantation: what is the evidence? Fertil Steril 105:873-84
Yoo, Jung-Yoon; Jeong, Jae-Wook; Fazleabas, Asgerally T et al. (2016) Protein Inhibitor of Activated STAT3 (PIAS3) Is Down-Regulated in Eutopic Endometrium of Women with Endometriosis. Biol Reprod 95:11