Regulation of Invasive Trophoblast Cell Lineage Development
Regulation of Invasive Trophoblast Cell Lineage Development
批准号:
10525942
负责人:
Kaela Margaret Varberg
金额:
$13.07万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-08-02 至 2024-07-31
关键词:
Abnormal placentationAdultAffectBHLH ProteinBindingBiological AssayCell Differentiation processCell LineCell LineageCellsCellular AssayChIP-seqChildChromatinCritical PathwaysDNA MethylationDataDevelopmentDiseaseEarly DiagnosisEmbryoEnsureEnvironmentEpigenetic ProcessFamilyFetal Growth RetardationFetusFoundationsGenesGenomicsGoalsGrantHealthHi-CHomologous GeneHumanImpairmentKansasLeadLifeMediatingMedical centerMentorsModelingModificationMolecularMolecular ConformationMorbidity - disease rateMothersNutrientPhasePhysiologicalPlacentaPlacentationPre-EclampsiaPredispositionPregnancyPregnancy ComplicationsPregnancy lossPremature BirthProtocols documentationPublicationsRattusRegulationRegulatory ElementResearchResearch InstituteResearch Project GrantsResistanceResourcesSeriesSignal PathwaySpiral Artery of the EndometriumTechniquesTestingTrainingTransposaseUniversitiesUterusVascular blood supplyVascular remodelingWorkWritingadverse outcomeadverse pregnancy outcomebisulfite sequencingcareerchromosome conformation captureearly detection biomarkerseffective interventionepigenomicsfetalgene regulatory networkimprovedin vivoinnovationknock-downlentiviral-mediatedmethylation patternmortalitymutantnovelpostnatalpregnancy disorderprogenitorresponsesingle-cell RNA sequencingskill acquisitionskillssmall hairpin RNAtranscription factortrophoblasttrophoblast stem cellwhole genome
中文摘要
项目摘要/摘要
英文摘要
Project Summary / Abstract
Uterine vascular remodeling occurs during gestation to meet increasing fetal nutrient demands. This
remodeling includes modification of the uterine spiral arteries into low resistance vessels for supplying blood to
the fetus. Central to uterine spiral artery remodeling are invasive trophoblast cells, known in the human as
extravillous trophoblast (EVT). Impaired EVT development leads to suboptimal fetal conditions and adverse
pregnancy outcomes including pregnancy loss, preeclampsia, intrauterine growth restriction, and preterm birth.
We identified a critical and conserved regulator of EVT lineage development, Achaete-Scute Family Basic
Helix-Loop-Helix Transcription Factor 2 (ASCL2). Depletion of ASCL2 in human trophoblast stem (hTS) cells
inhibits EVT formation. Similarly, global depletion of ASCL2 in vivo disrupts placental development and causes
embryonic lethality in the rat. However, the molecular mechanisms by which ASCL2 directs EVT lineage
development are unknown. Our established hTS cell lines and protocols for generating mutant rat models will
allow us to directly test our central hypothesis that ASCL2 controls EVT lineage development during
placentation. To investigate higher order actions of ASCL2 on the epigenomic landscape of the EVT cell
lineage, we will identify how ASCL2 depletion alters DNA methylation, chromatin accessibility and
conformation using whole genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin-
sequencing (ATAC-seq), and chromatin capture using Hi-C, respectively (Aim 1A). To identify direct genomic
targets of ASCL2 we will perform chromatin immunoprecipitation sequencing (ChIP-seq) in EVT cells (Aim
1B). ASCL2 regulation of trophoblast development and invasion will then be evaluated in vivo using our proven
techniques to generate rat hypomorphs (Aim 2A). To examine ASCL2-positive trophoblast cell development in
normal and diseased rat placentas we will conduct single cell RNA-sequencing (scRNA-seq) and single cell
ATAC-seq (Aim 2B). The proposed research plan will provide the candidate with a body of experimental work
necessary for independent publications and preliminary data for R-series grants. The candidate will utilize the
expertise of the co-mentoring team as well as resources at the University of Kansas Medical Center and
Children’s Mercy Research Institute for cultivation of professional development skills. These skills will be
improved through trainee mentoring, data presentation, and scientific writing. During the R00 phase the
candidate will develop independence from her mentors by identifying targets of ASCL2 and investigating their
contributions to invasive trophoblast lineage development with innovative rat models. The proposed research
project serves as the foundation for the candidate’s long-term career goal of identifying how dysregulated spiral
artery remodeling leads to a spectrum of diseases ranging from fetal growth restriction to preeclampsia.
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Regulation of Invasive Trophoblast Cell Lineage Development
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批准号:10927538
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项目类别:
-
资助金额:$24.9万
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财政年份:2023
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负责人:Kaela Margaret Varberg
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依托单位:
Regulation of Invasive Trophoblast Cell Lineage Development
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批准号:10675052
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项目类别:
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资助金额:$1.09万
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财政年份:2022
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负责人:Kaela Margaret Varberg
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依托单位:
Supplement (Covid) to Regulation of endovascular trophoblast cell development and uterine spiral artery remodeling
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批准号:10457641
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项目类别:
-
资助金额:$3.52万
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财政年份:2021
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负责人:Kaela Margaret Varberg
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依托单位:
Administrative Supplement to Regulation of endovascular trophoblast cell development and uterine spiral artery remodeling
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批准号:10388595
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项目类别:
-
资助金额:$0.25万
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财政年份:2021
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负责人:Kaela Margaret Varberg
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依托单位:
Regulation of endovascular trophoblast cell development and uterine spiral artery remodeling
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批准号:10063438
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项目类别:
-
资助金额:$6.86万
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财政年份:2018
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负责人:Kaela Margaret Varberg
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依托单位:
Regulation of endovascular trophoblast cell development and uterine spiral artery remodeling
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批准号:9769510
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项目类别:
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资助金额:$6.53万
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财政年份:2018
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负责人:Kaela Margaret Varberg
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依托单位:
海外基金