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Dynamics of FGF and its integration with other pathways during human germ layer differentiation

人类胚层分化过程中 FGF 的动态及其与其他途径的整合

基本信息

批准号：
10674713
负责人：
Kyoung Ha Jo
金额：
$ 8.08万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674713
关键词：
BMP4 Biological Models Cell Differentiation process Cell Fate Control Cell Line Cells Clustered Regularly Interspaced Short Palindromic Repeats Data Defect Development Down-Regulation Doxycycline Embryo Embryonic Development Endoderm Failure Fibroblast Growth Factor Genetic study Geometry Germ Layers Heparin Human Human Development Immunofluorescence Immunologic In Situ Hybridization In Vitro Infertility Knock-out Knowledge Lead Ligand Binding Ligands Logic Measures Mediating Mesoderm Modeling Mus Nodal Organ Organoids Outcome Pathway interactions Pattern Population Primitive Streaks Proteoglycan RNA Regenerative Medicine Regulation Resolution Role Series Signal Pathway Signal Transduction Small Interfering RNA Sulfatases Sulfate System Testing Therapeutic Uses Time Visceral Visualization WNT3 gene base blastocyst cell fate specification combinatorial differential expression differentiation protocol drug testing early embryonic stage experimental study gain of function gastrulation human pluripotent stem cell improved in vivo inhibitor insight loss of function novel receptor receptor binding single-cell RNA sequencing spatiotemporal sulfotransferase

项目摘要

Abstract Gastrulation is the stage of early embryonic development during which the body plan is established. Using the mouse as a model, it has been established that mammalian gastrulation is primarily regulated by BMP, FGF, WNT, and NODAL signaling pathways and disruption of these pathways can lead to developmental defects or early embryonic lethality which ay infest as infertility. However, it remains unclear how cells interpret multiple signaling pathways to make specific cell fate decisions. Moreover, findings in mice cannot directly be compare to human development. For example, disruption of FGF signaling at blastocyst stage leads to defects in visceral endoderm development in mice but not in human. Human pluripotent stem cells (hPSCs) have been an ideal model system to study gastrulation because they mimic many aspects of gastrulation and allow for high throughput, quantitative analysis and time resolved experiments in vitro. Using micropatterned hPSC gastrulation model and directed primitive streak like cell differentiation model, my data suggests that higher FGF/ERK signaling activity is spatially restricted to PSLCs and functional experiments that block FGF signaling results in a failure of PSLC differentiation as well as downregulation of WNT3 ligand expression. Based on this, my overarching hypothesis is that FGF/ERK signaling is spatially and temporally regulated by expression of FGF ligands and heparin sulfate proteogylcan (HSPG) modulators and act in parallel to BMP upstream of WNT and NODAL to create combined signaling patterns that induce different cell fate outcome. I will test this hypothesis by 1) determining how FGF activity is spactially and temporally regulated by FGF ligands and HSPG modulators, 2) dissecting the dynamics of multiple signaling activity underlying cell fate acquisition during in vitro gastrulation.

摘要