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.
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.
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