The overall objective of this proposal is to define the essential molecular mechanisms that underlie the preparation of the uterus to support pregnancy, in general, and specifically, the involvement of the orphan nuclear receptor transcription factor, COUP-TF II, in this process. Utilizing the progesterone receptor knockout, PRKO, mouse in combination with DNA microarray technology, we have identified the Indian Hedgehog, Ihh, morphogen pathway as being one of the earliest pathways responsive to progesterone. One of the downstream targets of the Ihh pathway is the orphan nuclear receptor transcription factor, COUP-TF II. In the mouse, COUP-TF II expression is initiated in the sub-epithelial stroma of the endometrium prior to the window of receptivity for embryo implantation and if pregnancy is established during the decidual transformation of the endometrial stroma cells. Functionally, COUP-TF II is a critical factor regulating development. Ablation of COUP-TF II in mice results in early embryo lethality. Mice heterozygous for ablation of COUP-TF II are sub-fertile partially due to impairment of the ability of the uterus to support implantation. In humans, DNA microarray analysis of endometrial biopsy tissue demonstrated that, similar to the mouse, COUP-TF II expression is increased in the human uterus during the implantation period. COUPTF II expression has also been observed in endometriotic tissue and has been hypothesized to play a protective role in regulating hormone production and growth of this diseased tissue. These laboratory and clinical observations indicate that COUP-TF II plays an important role in normal uterine function and in regulating uterine biology in diseased states. Given the critical role COUP-TF II plays in mouse uterine biology, as well as its expression at critical times in the human endometrium, this proposal will translate these laboratory findings into an investigation of the regulation and role of COUP-TF II in the human uterus during pregnancy and in pathological states. This will be accomplished by the following: 1. Defining the stage and cell specific pattern of COUP-TF II in the human endometrium; 2. Determining the paracrine and endocrine regulation of COUP-TF II expression in human endometrial stromal cells; 3. Determining the role of COUP-TF II in the regulation of endometrial stromal function; 4. Identifying the molecular pathways regulated by COUP-TF II in the endometrial stroma cells.
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