An estimated 25%-60% of all conceptions end in pregnancy failure depending upon the mammalian species. Recurrent pregnancy loss, defined as two or more consecutive failed pregnancies, is a common complication to pregnancy in women that affects more than 1% of pregnancies. Epidemiological studies in humans and livestock, as well as genetic studies in model organisms, support the notion that failed pregnancy occurs due to faulty uterine function or miscommunication between the embryo and mother during implantation. While much research effort has been poured into understanding complications that occur later in pregnancy, only minimal consideration has been given to the problems that occur during the establishment of pregnancy. Paradoxically, most pregnancies fail during embryo implantation, long before development of the fetal placenta. As such, one of the major research themes in our lab is to understand how the embryo coordinates changes in the mother, both locally within the uterus, as well as systemically (i.e., modulation of the maternal immune system) to allow for the successful establishment of pregnancy. We recently established that in response to the implanting embryo, the uterus takes on a non-erythroid hemoglobin biosynthetic function. We have identified the transcriptional regulatory mechanism by which this occurs and feel the studies have tremendous potential to increase our understanding of how the embryo modifies the maternal system to allow the semi-allogenic embryo to survive within the mother without rejection. We are also working toward increasing knowledge related to the molecular events that transform endometrial stromal cells into epithelial-like decidual cells that perform a multitude of function as the embryo implants.
Dysfunction of the uterus is a common factor affecting the quality of life and morbidity/mortality of the human female. Over 60,000 women (USA) are diagnosed with endometrial cancer annually, and endometriosis, which often results in infertility, affects up to 12% of all reproductive aged women with annual costs of about $22 billion. Incomplete uterine involution following parturition is a major impediment to reestablishing pregnancy in dairy cattle, a persistent problem that costs the dairy industry millions of dollars annually. Recent advances in stem cell biology have made it clear that most tissues exhibit renewal via adult stem cells. Using a combination of transgenic, transplantation and molecular biology approaches, we have established that the uterus harbors unique populations of adult stem/progenitor cells within the stromal and epithelial compartments. Considering that insufficient endometrial thickening is a major hurdle for establishing a successful pregnancy, particularly in an in vitro fertilization (IVF) setting, studies of endometrial stem cells are of likely importance to fertility in mammals. Through the elucidation of mechanisms that coordinate stem cell activation and subsequent tissue growth, basic studies of uterine stem/progenitor cell biology will likely have practical application in developing therapeutic remedies for hyperproliferative diseases of the uterus like endometriosis and endometrial cancer.
Progesterone is the hormone of pregnancy. It is well-established from pharmacological studies in diverse mammalian species and mouse mutagenesis studies that the classical nuclear progesterone receptor mediates many of the actions of progesterone. However, activation of this classical receptor does not account for all of the actions of progesterone. We are interested in identifying and characterizing the molecular machinery by which progesterone signals outside of the classical pathway. Using mutant mouse models generated by our lab, we have demonstrated that progesterone receptor membrane component (PGRMC) 1 and PGRMC2 are necessary for normal fertility in the female, as well as proper hormone signaling in the uterus. Furthermore, our lab has demonstrated that increased expression of PGRMC1 contributes to the growth, progression, and chemoresistance of women’s reproductive cancers (e.g., endometrial, ovarian and breast). We are now focused on understanding the mechanism by which PGRMC1 and PGRMC2 function in reproductive tissues and how they mediate progesterone signaling events. At the moment, we are testing the hypothesis that PGRMC1 and PGRMC2 regulate proliferative events in the female reproductive tract. Pathways that may be regulated by PGRMC1 and PGRMC2 are those that regulate proliferation, mRNA processing, and cellular energy homeostasis.
