A new animal model for investigating the invasive trophoblast lineage

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PROJECT SUMMARY/ABSTRACT The placenta plays a crucial role during pregnancy ensuring fetal growth and development. Successful pregnancy hinges upon placental adaptations to the maternal environment. The human placenta is classified as hemochorial and is characterized by extensive intrauterine trophoblast cell invasion. During the course of the gestation, invasive trophoblast cells or extravillous trophoblast, as they are referred to in humans, migrate from the placenta into the uterine parenchyma where they act to anchor the placenta to the uterus and remodel uterine spiral arteries. Uterine vascular remodeling is central to providing adequate nutrient flow to the fetus and normal fetal development. Abnormalities in the organization and structure of trophoblast cell populations are associated with pregnancy disease states. Shallow trophoblast invasion and aberrant modification of the uterine vasculature are directly linked to preeclampsia, early pregnancy loss, intrauterine growth restriction, pre-term birth, and placental abruption. On the other hand, excessive trophoblast invasion, as in disorders such as placenta accreta, jeopardizes pregnancy, maternal health, and future-child bearing. Molecular events that trigger the differentiation of invasive trophoblast cell lineages and trophoblast-guided uterine spiral artery remodeling are poorly understood. Experimental tools are in-hand to identify candidate regulators of the invasive trophoblast cell lineage and to test their physiological relevance. Placentation in the rat is characterized by extensive intrauterine trophoblast invasion and trophoblast-guided spiral artery remodeling resembling developmental processes evident in human placentation. Global genome-editing in the rat is an effective tool for investigating a sub-set of candidate genes implicated in regulating deep placentation but not all candidate genes regulating deep placentation. Some genes possess multiple roles in embryogenesis, precluding an evaluation of a specific role in the invasive trophoblast cell lineage. The generation of a conditional allele circumvents this issue. In the proposed research, we will generate a rat model for generating invasive trophoblast-lineage specific conditional alleles using Crispr/Cas9 genome editing. In this project, we generate a transgenic rat model expressing Cre recombinase in invasive trophoblast cells under control of Prl7b1 regulatory sequences and validate the Prl7b1- Cre driver rat strain. The proposed experiments will provide valuable new tools for the scientific community to discern roles for candidate genes in the regulation of trophoblast invasion and trophoblast-guided uterine spiral artery remodeling, and thus a novel experimental paradigm to explore the etiology of high-risk pregnancies.