The overall goal of this proposal is to determine the P-regulated genes that are involved in the proper maturation of the primate endometrium.. Our studies will use an in vivo primate model (rhesus monkey) that will serve as an appropriate bridge to the human. Our ability to produce artificial menstrual cycles in ovariectomized rhesus monkeys provides us the experimental means necessary to analyze in detail endometrial response to progesterone (P). In vivo studies in this primate model are required because the complexity of the endometrium cannot at present by studied appropriately in isolation. We envisage that coordinated, steroid- induced activation and repression of many genes during the changeover from E to P-dominance is important for correct endometrial maturation. Our approaches will combine modern cell and molecular techniques to analyze endometrial response to P in an in vivo physiological model e.g. PCR analysis, subtractive hybridization, DDRT- PCR, DNA sequencing, laser capture microdissection etc. We propose three specific aims to complement and extend our previous findings: 1) to identify and characterize genes and gene fragments whose expression (up-regulation or repression) is restricted to the expected window of receptivity i.e. days 17-26: 2) to use laser capture microdissection to study P-regulated genes with the morphological unit primarily associated with implantation i.e. to include an identification of the 5' flanking promoter region. Luteal phase defects are purported to be the most common endocrinopathy in women with infertility, recurrent aboration or undergoing ovulation induction. In addition, our previous studies have identified PO-dependent candidate tumor suppressors that may provide a molecular link to the protective effect of P on unopposed E exposure in reproductive tract cancers in women. The studies designed herein can potentially provide important insights into the genes that are involved in disorders of female fertility, endometrial hyperplasia, and reproductive tract cancer.
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