Coordinated control of the synergistic and antagonistic actions of estrogen (E2) and progesterone (P4) is required to achieve endometrial receptivity and successful embryo implantation. Steroid receptor coregulator-2 (SRC-2), a member of the SRC family of coregulators, is essential for murine endometrial receptivity and decidualization. SRC-2 can act as a coactivator or as a corepressor of P4 receptor (PR) mediated transcriptional responses in the murine uterus. Importantly, recent studies show that (a) SRC-2 is expressed in the same endometrial cell-types in the human as observed in the mouse;(b) knockdown of SRC-2 blocks the decidualization of human endometrial stromal cells in culture;and (c) dysregulation of normal SRC-2 expression is observed in the eutopic endometrium of patients diagnosed with endometriosis. Together, these findings suggest that SRC-2 represents a potent coregulator of steroid hormone-dependent endometrial function in the human, and that its dysregulation may be linked to endometrial pathologies, such as endometriosis. Based on the aforementioned, the following hypothesis is proposed: Steroid receptor coregulator-2 is an essential coregulator of P4 signaling which controls proliferative and differentiatlve programs required for endometrial receptivity and decidualization. To advance this hypothesis, we will (1) delineate the cellular and molecular mechanisms which underpin murine SRC-2 action in normal endometrial responses to steroid hormone exposure;(2) define the importance of human SRC-2 in normal endometrial responses to steroid hormone exposure;(3) establish the importance of unscheduled upregulation of SRC-2 expression in the breakdown of normal P4 induced endometrial responses that are required for the establishment of pregnancy;and (4) determine the role of SRC-2 in P4 control of endometriotic lesion growth. State-of-the-art mouse genetics, lentiviral technology to deregulate SRC-2 expression in an innovative experimental model for human endometrial function and endometriosis, and judiciously designed transcript profiling and microRNA array approaches will constitute a number of the inventive methodologies that will be used to successfully execute our stated aims. By addressing the limitations of conventional methods, this research program will significantly expand the field of endometrial coregulator study far beyond the current descriptive mode of analysis to a more interrogative field of investigation. Results from these studies promise not only to further our understanding of endometrial coregulator function but also aid in the design of novel diagnostic approaches and/or therapies for infertility.
From a clinical standpoint, the indispensable role of SRC-2 in murine peri-implantation biology demands further study in the human since implantation failure is a key factor that undermines pregnancy establishment. Beyond providing critical mechanistic insights into the coregulator role of SRC-2 In endometrial function and disease, the above aims are predicted to contribute to improved treatment strategies for female endometrial disorders that cause pain and infertility.
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