Dissecting Uterine Progesterone Resistance

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DESCRIPTION (provided by applicant): Progesterone is a steroid hormone with important actions on the female reproductive tract that are essential for reproduction. Among these key actions are stimulation of uterine endometrial stromal cell proliferation and differentiation. Failure in the ability of the uterus to appropriately respond to progesterone (referred to as progesterone resistance) is a characteristic feature of a number of female reproductive tract disorders, including endometriosis, polycystic ovarian syndrome, endometrial hyperplasia/cancer, and early pregnancy loss. The barrier for progress in understanding the etiology of progesterone resistance is the availability of appropriate experimental models. The Brown Norway (BN) rat is an inbred strain and a newly discovered animal model for investigating progesterone resistance. BN rat progesterone resistance is remarkably similar to progesterone resistance described in various human female reproductive tract diseases. The goal of our proposed research is to elucidate cellular and molecular processes causing uterine progesterone resistance. We propose to investigate progesterone resistance in the BN rat. The proposed research efforts will provide information on molecular mechanisms underlying progesterone resistance, including the dissection of the contributions of individual chromosomes to the uterine progesterone resistance phenotype. Understanding molecular mechanisms underlying uterine progesterone resistance is a key to identifying developmentally sensitive events that are potentially susceptible to dysregulation; and represent opportunities for new scientific and applied pursuits, including the development of diagnostics and especially treatments for diseases stemming from progesterone resistance. PUBLIC HEALTH RELEVANCE: Progesterone is an essential hormone regulating uterine physiology. Progesterone resistance is associated with a variety of female reproductive tract disorders, including endometriosis, polycystic ovarian syndrome, endometrial hyperplasia, and early pregnancy loss. Elucidation of molecular mechanisms responsible for progesterone resistance is a key to understanding the etiology of uterine dysfunction and early pregnancy failure.