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Principal Investigator: Mikaela Elizabeth Simon
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2024
Award: $37,752
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY/ABSTRACT
During pregnancy, maternal and extraembryonic cells interact at the uterine-placental interface, facilitating
adaptations that promote fetal growth. Trophoblast stem (TS) cells differentiate and invade into the uterus
during pregnancy. When invasive trophoblast cells fail to invade and remodel the uterine spiral arteries this
leads to obstetrical complications such as early pregnancy loss, preeclampsia, intrauterine growth restriction,
and preterm birth. There is little known about the mechanisms of invasive trophoblast cell lineage
development. The long-term goal of our research is to identify conserved regulators of invasive trophoblast cell
lineage development and its contributions to diseases of pregnancy. We utilize the rat model because like the
human it exhibits deep intrauterine trophoblast cell invasion, unlike the shallow invasion observed in the
mouse. We also use human TS cells that can be manipulated to differentiate into invasive trophoblast cells,
which are known as extravillous trophoblast (EVT) cells in the human. Human TS are a useful model for
investigating molecular mechanisms regulating trophoblast cell differentiation. To identify candidate regulators
of the invasive trophoblast cell lineage, our lab performed single-cell RNA sequencing (scRNA-seq) of the rat
uterine-placental interface. We identified follistatin-like 3 (FSTL3) as a conserved transcript uniquely
expressed in invasive trophoblast cells of the rat and human. FSTL3 is an antagonist of activin signaling.
Evidence exists for activin and FSTL3 involvement in the regulation of trophoblast cell proliferation, survival,
migration, and invasion. In Aim1, we will utilize loss-of-function and gain-of-function approaches to investigate
the involvement of activin and FSTL3 in the regulation of human TS cell differentiation into the EVT cell
lineage. We will examine structural, transcriptomic, and functional processes affected by activin-FSTL3
dysregulation. In Aim 2, we will evaluate the role of FSTL3 in development of the invasive trophoblast cell
lineage within the rat hemochorial placenta. We have generated an FSTL3 null rat model using CRISPR/ Cas9
genome editing. These experiments will permit analysis of the regulatory role of FSTL3 in a physiological
context. 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 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 Reproductive and Developmental Sciences, and the Department of Pathology and Laboratory
Medicine at KUMC represent a rich scientific environment that will provide the applicant with outstanding
graduate training and a research opportunity to gain fundamental new insights into the regulation of female
fertility.
Terms: <Abate><Activin-Binding Protein><Activins><Address><Affect><Biological><Blood flow><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Growth in Number><Cell Interaction><Cell Lineage><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell-to-Cell Interaction><Cells><Cells Placenta-Tissue><Cellular Proliferation><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Common Rat Strains><Complex><Complex thinking><Critical Thinking><Decidua><Decidua Graviditas><Developing fetus><Development><Disease><Disorder><EPH Gestosis><Embryo><Embryonic><Environment><Evaluative Thinking><Exhibits><FSH-Releasing Protein><Fetal Development><Fetal Growth><Fetal Growth Restriction><Fetal Growth Retardation><Fetus><Follistatin><Genomics><Gestation><Goals><Health><Hemochorial Placental Development><Hemochorial Placentation><Human><IUGR><In Vitro><Intracellular Communication and Signaling><Intrauterine Growth Retardation><Invaded><Kansas><Laboratories><Location><Medical center><Medicine><Mentors><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mothers><Murine><Mus><Normal Placentoma><Nutrient><Pathogenesis><Pathology><Physiologic><Physiological><Physiology><Placenta><Placenta Embryonic Tissue><Placental Development><Placentation><Placentome><Population><Pre-Eclampsia><Preeclampsia><Pregnancy><Pregnancy Complications><Pregnancy Toxemias><Premature Birth><Prematurely delivering><Preterm Birth><Process><Proteinuria-Edema-Hypertension Gestosis><Rat><Rats Mammals><Rattus><Regulation><Regulatory Pathway><Research><Rodent><Rodentia><Rodents Mammals><Role><Science><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Site><Spiral Artery><Spiral Artery of the Endometrium><Study models><Therapeutic Intervention><Training><Transcript><Universities><Uterus><Villous><antagonism><antagonist><biologic><biological signal transduction><candidate identification><cellular differentiation><complications during pregnancy><developmental><diagnostic development><early pregnancy loss><embryo cell><experiment><experimental research><experimental study><experiments><female fertility><gain of function><genome editing><genomic editing><impaired fetal growth><in vivo><insight><intervention therapy><intra-uterine growth><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth><intrauterine growth restriction><loss of function><migration><mutant><obstetrical complication><pre-eclamptic><pregnancy toxemia/hypertension><pregnancy-related complications><premature childbirth><premature delivery><prenatal growth disorder><preterm delivery><progenitor cell differentiation><progenitor differentiation><reproductive><restraint><scRNA-seq><shear stress><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skills><social role><stem><stem and progenitor differentiation><stem cell differentiation><transcriptomics><trophoblast><trophoblast progenitor><trophoblast progenitor cell><trophoblast stem cell><womb>