The long-term objective of Ihis a~l icatiuJl is to better understand the phenomenon of progesterone resistance in endometriosis in order to develop alternate therapies for this disease. The action of progesterone receptor (PR) in the physiological context remains unclear and this study aims at elucidating novel mechanisms of action in partnership with a specific transcription factor FOXOI . This protein has been shown to be a critical regulator during endometrial differentiation. specifically deciduaijzation, as well as regulate many c.e~l~ar processes associated with the ce:1 proliferation, oxidative stress, differentiation, and apoptosis. Given that FOX01 expression is severly decreased in ectopic endometrial tissue in women with endometriosis, we propose that progesterone signaling is abnormal in these cells promoting FOX01 degrad3tion. This would then lead to proliferation and survival of endometriotic cells. This proposal consists of two aims.
Specific aim 1 will explore the role of progestins in the diminished FOXOt expression in endometriotic stromal cells.
Specific aim 2 will look at harboring human endometriotic tissues under t~.e kidney capsule of SelD mice in order to study progesterone responsiveness in an in vivc system. This model """"""""'ill also be used to test ,In Akt inhibitor to promote death.
These aims will increase the understanding of progesterone resistance in endometriosis as well as investigate the use of targeted biological agents as an alternate treatment for endometriosis.

Public Health Relevance

Endometriosis affects more than 10% of women and is highly associated with infertility. While progesterone antagonizes estrogen-mediated growth in the normal endometrium, endometriotic tissues are usually unresponsive to progesterone. We will study the interaction of progesterone receptor with the forkhead transcription factor, FOXO1, which is an important molecule in the endometrium and is significantly diminished in endometriosis. We will use chemical compounds to restore FOXO1 expression in order to promote apoptosis in endometriotic cells in vitro and in vivo. These studies will contribute to understanding the molecular mechanisms of endometriosis in order to provide a new opportunity for the development of alternate and combinatorial therapies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044715-07
Application #
7937726
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Project Start
2003-09-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
7
Fiscal Year
2010
Total Cost
$381,250
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
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
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

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