Saturday, April 20, 2024
4/20/2024
As pregnancy progresses, the oxygen and nutrient needs of the growing fetus increase. To accommodate these needs, adaptations occur at the uterine-placental interface. Early in pregnancy, trophoblast stem (TS) cells differentiate and invade into the uterine tissue to facilitate remodeling of uterine spiral arteries. Abnormal placenta development with insufficient trophoblast invasion leads to pregnancy disorders including early pregnancy loss, preeclampsia, intrauterine growth restriction, and pre-term birth. The failure of invasive trophoblast cell transformation of the uterus and especially the uterine vasculature is the causative event leading to these devastating obstetrical complications. However, we know little about the mechanisms underlying development of the invasive trophoblast cell lineage. The underlying premise of our research approach is that conservation exists in the regulation of placentation. We utilize the rat as a model because unlike other species, including the mouse, the rat exhibits deep intrauterine trophoblast cell invasion similar to the human. Human TS cells have recently been isolated and propagated in vitro and can be manipulated to differentiate into invasive trophoblast, which in the human are referred to as extravillous trophoblast (EVT) cells. Human TS cells are an excellent model for investigating molecular mechanisms regulating trophoblast cell differentiation. Our long-range goal is to identify conserved regulators controlling differentiation of the invasive trophoblast cell lineage. In a preliminary study, we used single-cell RNA sequencing (scRNA-seq) of the rat uterine-placental interface to identify candidate regulators of the invasive trophoblast cell lineage. We identified cyclin dependent kinase inhibitor 1C (CDKN1C) as a conserved transcript uniquely expressed in invasive trophoblast cells of the rat and human. CDKN1C is a key regulator of cell proliferation, endoreduplication, and differentiation in several developmental systems. In Aim 1, a loss-of-function approach will be used to investigate the involvement of CDKN1C in human TS cell differentiation into the invasive EVT cell lineage. We will examine structural, transcriptomic, and functional processes impacted by CDKN1C. In Aim 2, we utilize a loss-of-function rat model to examine the role of CDKN1C in the physiological context of placentation. This project will be completed at the University of Kansas Medical Center (KUMC) under the guidance of Dr. Michael J Soares and a mentoring team of outstanding biomedical scientists. A training plan has been formulated to facilitate the development of technical proficiencies and critical thinking skills necessary to devise and execute experimentation that effectively addresses a meaningful biological question. The Soares Laboratory, the Institute for Reproduction and Perinatal Research, and the Department of Pathology and Laboratory Medicine at KUMC represent a rich scientific environment that will provide outstanding graduate training and a research opportunity to gain new insights into the regulation of the invasive trophoblast cell lineage and the establishment of the uterine-placental interface.
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