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Principal Investigator: Soumen Paul
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2024
Award: $426,397
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Abstract
Placental dysfunction leads to pregnancy-associated disorders, including intrauterine growth restriction
(IUGR) and preeclampsia, and also serves as a developmental cause for postnatal and adult diseases. Often,
the causal alterations in the placentation process, which lead to defective pregnancies, occur early in
gestation. Defective development and differentiation of trophoblast progenitors are leading causes for
pathological pregnancies. However, we have a poor understanding of molecular mechanisms that regulate
trophoblast progenitor self-renewal, differentiation and function in postimplantation embryos. Studies on
mutant mouse models and mouse trophoblast stem cells (mouse TSCs) implicated lysine-specific demethylase 1
(LSD1), the first identified histone demethylas, as a critical regulator to prevent premature differentiation of mouse
TSCs. However, the importance of LSD1 in the context of differentiated trophoblast cells of a matured placenta is
yet to be defined. Also, the importance of LSD1 in human trophoblast development has never been tested. Our
preliminary findings establish that LSD1 expression is conserved in trophoblast progenitors across mammalian
species, including humans. Thus, in this proposal we will investigate importance of LSD1 in the development of
specialized trophoblast cells, namely syncytiotrophoblasts (SynTBs) and invasive trophoblasts, at the maternal-
fetal interface. We will also define importance of LSD1 in human trophoblast differentiation and interrogate LSD1
function.
Two specific aims are proposed. Aim 1 will study Lsd1 conditional knockout mouse model to test the
hypothesis that cell-autonomous function of LSD1 in lineage-specific trophoblast progenitors ensures
establishment of differentiated SynTBs and invasive trophoblast cells at the maternal-fetal interface.
In Aim 2, using CTB-derived human trophoblast stem cells, we will test the hypothesis that LSD1
establishes a conserved gene expression program in mouse and human trophoblast progenitors and impairment
of LSD1-dependent transcriptional program will impair self-renewal and differentiation potential of human
trophoblast progenitors. In addition, we will also interrogate significance of LSD1-dependent mechanisms in the
context of pathological pregnancies.
Terms: <21+ years old><AOF2><ASCL2><ASCL2 gene><Adult><Adult Human><Adverse effects><Antigen Defined by Monoclonal Antibody AUAI><BLIMP1><Blastocyst Implantation><Blastosphere><Cell Body><Cell Lineage><Cells><Cells Placenta-Tissue><Chorion><Conceptus><Cone><Defect><Development><Disease><Disorder><Dysfunction><EPH Gestosis><Ectoderm><Embryo><Embryo Implantation><Embryonic><Ensure><EpCAM><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cellular Adhesion Molecule><Fetal Growth Restriction><Fetal Growth Retardation><Functional disorder><GA733-2><GCM1><GCM1 gene><GCMA><Gastrointestinal Tumor-Associated Antigen 2, 35-KD Glycoprotein><Gene Expression><Gene Transcription><Genetic Transcription><Gestation><Glial Cells Missing, Drosophila, Homolog of, 1><Glycogen><Histones><Human><IUGR><Impairment><Infant Health><Internal Ear><Intrauterine Growth Retardation><KDM1A><KDM1A gene><KO mice><Knock-out Mice><Knockout Mice><LSD1><Labyrinth><Lysine-Specific Demethylase 1><Lysine-Specific Demethylase 1A><M4S1><MIC18><Maintenance><Maternal Health><Maternal-Fetal Exchange><Mediating><Membrane Component, Chromosome 4, Surface Marker 1><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Nidation><Normal Placentoma><Null Mouse><Ovum Implantation><PRDI-BF1><PRDM1><PRDM1 gene><Parietal><Pathogenesis><Pathologic><Pathway interactions><Physiopathology><Placenta><Placenta Embryonic Tissue><Placental Development><Placentation><Placentome><Population><Pre-Eclampsia><Preeclampsia><Pregnancy><Pregnancy Toxemias><Pregnancy loss><Preimplantation Embryo><Premature Birth><Prematurely delivering><Preterm Birth><Process><Proteinuria-Edema-Hypertension Gestosis><Public Health><RNA Expression><Reproduction><Research><Role><Specific qualifier value><Specified><Spiral Artery><Spiral Artery of the Endometrium><Stem Cell like><Syncytiotrophoblast><TACSTD1><TACSTD1 gene><Testing><Transcription><Transplacental Exposure><Tumor-Associated Calcium Signal Transducer 1><Villous><adulthood><blastocyst><blastula><conditional knock-out><conditional knockout><cytotrophoblast><developmental><early pregnancy loss><embryo attachment><epigenetically><fetal><gene conservation><histone demethylase><impaired fetal growth><implantation><inner ear><insight><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth restriction><maternal-fetal interface><mouse model><murine model><mutant mouse model><natural Blastocyst Implantation><pathophysiology><pathway><postnatal><pre-eclamptic><pre-implantation embryo><pregnancy toxemia/hypertension><premature><premature childbirth><premature delivery><prematurity><prenatal growth disorder><preterm delivery><prevent><preventing><progenitor><progenitor cell population><progenitor cell regeneration><progenitor cell self renewal><progenitor population><progenitor regeneration><progenitor self renewal><programs><self-renew><self-renewal><social role><stem and progenitor cell population><stem and progenitor cell regeneration><stem and progenitor cell self renewal><stem cell characteristics><stem cell population><stem cell regeneration><stem cell self renewal><stemness><trophoblast><trophoblast progenitor><trophoblast progenitor cell><trophoblast stem cell>