Investigating the Role of NKX2-1 in Early Human Lung Development Using an Induced Pluripotent Stem Cell (iPSC) Model
使用诱导多能干细胞 (iPSC) 模型研究 NKX2-1 在人类早期肺发育中的作用
基本信息
- 批准号:10708834
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 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:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptedAffectAlveolarAlveolar CellBindingBinding SitesBiological AssayBirthBrainCRISPR correctionCRISPR interferenceCell Differentiation processCell LineCellsCouplingDataDefectDevelopmentDiseaseDistalEpithelial CellsEpitheliumFlow CytometryGene ExpressionGenerationsGenesGeneticGenomicsHeterozygoteHomeoboxHumanHuman DevelopmentHypothyroidismKnockout MiceLaboratoriesLeadLinkLungLung AdenocarcinomaLung diseasesMaintenanceMalignant NeoplasmsMapsMolecularMutationNatural regenerationNeurologicPatientsPatternPhenotypePlayPluripotent Stem CellsPreparationProteinsProtocols documentationRegenerative MedicineResearch PersonnelResolutionRespiratory InsufficiencyRoleSpecific qualifier valueStomachStudy modelsSyndromeSystemTAC1 geneTechnologyTestingThyroid DiseasesThyroid GlandTimeTissue SampleTissuesUp-RegulationWorkalveolar type II cellcell typedeviantdifferentiation protocoldirected differentiationexperimental studyfetalgene functiongene regulatory networkgenetic manipulationhuman fetus tissuehuman tissueimmunocytochemistryin vivoinduced pluripotent stem celllentiviral-mediatedlung developmentmRNA sequencingmutantmutation correctionprogenitorprogramspulmonary functionsingle cell mRNA sequencingstem cell differentiationstem cell modelstem cellssurfactanttranscription factortranscriptometranscriptomic profilingtranscriptomicstumor progression
项目摘要
NK2 Homeobox 1 (NKX2-1) is a critically important transcription factor in lung
development, with all lung epithelia being derived from an NKX2-1+ progenitor pool. Nkx2-1
knockout mice have hypoplastic lungs, and humans with NKX2-1 mutations suffer from
respiratory insufficiency, hypothyroidism, and neurological problems, a disease known broadly
as brain-lung-thyroid syndrome. It is known that NKX2-1’s importance is derived from its ability
to influence the expression of downstream target genes, which include genes like surfactant
proteins and secretoglobins, which contribute significantly to lung function. Despite its known
importance, NKX2-1’s role in early human development is not fully defined.
Studies into early human development have been significantly hindered by difficulties in
access to human fetal tissue and issues with genetically manipulating fetal derived cells. A
recently developed technology that allows researchers to investigate early human development
is the induced pluripotent stem cell (iPSC) system, which allows for generation and subsequent
differentiation of stem cells to tissue types of choice. Our lab and others have developed
protocols to generate airway and alveolar cells from iPSCs, actively recapitulating development
along the way. Our group has also gained expertise in technologies to characterize and
manipulate our cells, including single cell transcriptomics and CRISPR interference (CRISPRi).
In this project, we seek to synergistically combine the components of this scientific toolbox to
study how NKX2-1 influences early human development.
Using our iPSC system, we seek to test the hypothesis that NKX2-1 plays a central role
in lung specification and patterning, and that the downstream targets of NKX2-1 are context
dependent and vary based on cell-type and developmental time point. We seek to do this
through genomic binding assays to identify NKX2-1 binding loci at several points in
development. In addition, we will perform single cell mRNA sequencing with an NKX2-1 mutant
cell line in comparison with an isogenic cell line with this mutation corrected. Using these two
approaches we hope to identify NKX2-1’s binding loci across development, and to observe the
molecular consequences that come with an NKX2-1 mutations. We also seek to modulate
expression of downstream targets of NKX2-1, including SOX2, TP63, and NKX2-1 itself to
further deduce the gene regulatory network by which NKX2-1 acts. Our iPSC-based model
allows for the unprecedented coupling of genetic manipulation and high-resolution
transcriptomics to further understand how a critical transcription factor influences development.
NK2同源盒1 (NKX2-1)是肺组织中一个至关重要的转录因子
项目成果
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{{ truncateString('Taylor Matte', 18)}}的其他基金
Investigating the Role of NKX2-1 in Early Human Lung Development Using an Induced Pluripotent Stem Cell (iPSC) Model
使用诱导多能干细胞 (iPSC) 模型研究 NKX2-1 在人类早期肺发育中的作用
- 批准号:
10537255 - 财政年份:2022
- 资助金额:
$ 4.77万 - 项目类别:
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