The long-term objective of this application is to better understand the dynamic interaction that occurs between the conceptus and the mother that allow for the establishment and maintenance of pregnancy. The major focus of our research is on the molecular events that occur in the endometrium in response to early embryonic signals and the invading trophoblast. Aberrant expression of genes in the endometrium during this time is detrimental to the maintenance of pregnancy and could lead to miscarriages, spontaneous abortions and infertility. In response to pregnancy hormones and conceptus factors, the endometrium undergoes a major transformation, termed decidualization. During this process, the stromal cells of the endometrium express important genes. This study focuses on the regulation of a major secretory product of the decidualizing stromal cells, insulin-like growth factor binding protein-1 (IGFBP-1). IGFBP-1 modulates the actions of insulin-like growth factors (IGFs) which are critical during early pregnancy and can act independently of IGFs to regulate trophoblast invasion. Recently, we demonstrated that two transcription factors, FKHR and HOXA10, which have been demonstrated to be important in reproductive processes, interact with one another and up regulate the IGFBP-1 promoter in a cooperative manner in endometrial stromal cells. Based on this novel data, studies have been designed to further delineate the mechanisms involved in the cooperative up regulation of the IGFBP-1 promoter by FKHR and HOXA10.
In aim 1 the binding sites of FKHR and HOXA10 on the IGFBP-1 promoter are identified. With the use of a powerful new technique, chromatin immunoprecipitation (CHIP), the binding sites for endogenous FKHR and HOXA10 proteins on the endogenous IGFBP-1 gene within the chromatin in the decidualized stromal cells are determined. This technique allows one to study interaction of transcription factors with the chromatin as they occur in situ.
In aim 2, characterization of FKHR and HOXA10 and determination of binding sequences on the IGFBP-1 gene in cells originating from non-pregnant and pregnant baboon endometrium will be performed by taking """"""""snapshots"""""""" of the cells and tissue using formaldehyde cross linking. These studies will demonstrate the influence of the conceptus on FKHR and HOXA10 expression and their activation of the IGFBP-1 gene.
In aim 3, FKHR and HOXA10 expression and activity in the endometrium of baboons with endometriosis will be studied. The objective of aim 3 is to determine why FKHR and HOXA10 do not significantly activate the IGFBP-1 promoter. The stromal cells from baboons with endometriosis are obviously different from that of a normal animal. These studies will give a better understanding of the molecular events that may be associated with increased implantation failure in women with endometriosis. The three aims in this application will provide valuable insights into the molecular dynamics of the endometrium in response to pregnancy. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044715-03
Application #
6772475
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Yoshinaga, Koji
Project Start
2003-07-07
Project End
2007-05-31
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$238,320
Indirect Cost
Name
Northwestern University at Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kim, Tae Hoon; Yu, Yanni; Luo, Lily et al. (2014) Activated AKT pathway promotes establishment of endometriosis. Endocrinology 155:1921-30
Kim, J Julie; Kurita, Takeshi; Bulun, Serdar E (2013) Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev 34:130-62
Eaton, Jennifer L; Unno, Kenji; Caraveo, Marshall et al. (2013) Increased AKT or MEK1/2 activity influences progesterone receptor levels and localization in endometriosis. J Clin Endocrinol Metab 98:E1871-9
Yin, Xunqin; Pavone, Mary Ellen; Lu, Zhenxiao et al. (2012) Increased activation of the PI3K/AKT pathway compromises decidualization of stromal cells from endometriosis. J Clin Endocrinol Metab 97:E35-43
Bulun, Serdar E; Cheng, You-Hong; Pavone, Mary Ellen et al. (2010) Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med 28:36-43
Ward, Erin C; Hoekstra, Anna V; Blok, Leen J et al. (2008) The regulation and function of the forkhead transcription factor, Forkhead box O1, is dependent on the progesterone receptor in endometrial carcinoma. Endocrinology 149:1942-50
Lu, Z; Hardt, J; Kim, J J (2008) Global analysis of genes regulated by HOXA10 in decidualization reveals a role in cell proliferation. Mol Hum Reprod 14:357-66
Jackson, Kevin S; Brudney, Allison; Hastings, Julie M et al. (2007) The altered distribution of the steroid hormone receptors and the chaperone immunophilin FKBP52 in a baboon model of endometriosis is associated with progesterone resistance during the window of uterine receptivity. Reprod Sci 14:137-50
Kim, J Julie; Taylor, H S; Lu, Z et al. (2007) Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod 13:323-32
Takano, Masashi; Lu, Zhenxiao; Goto, Tomoko et al. (2007) Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells. Mol Endocrinol 21:2334-49

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