Epigenetic mechanisms of gene regulation in nephron progenitor cell proliferation and differentiation
肾单位祖细胞增殖和分化基因调控的表观遗传机制
基本信息
- 批准号:10442628
- 负责人:
- 金额:$ 42.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAreaBackBindingCell Differentiation processCell LineageCellsChildhoodChromatinChromatin Remodeling FactorChronic Kidney FailureComplementComplexCongenital AbnormalityCuesDeacetylaseDefectDevelopmentDiseaseDistalEmbryoEndowmentEnhancersEpigenetic ProcessEpithelial CellsEquilibriumEventFunctional disorderGene ExpressionGene Expression ProfileGene Expression RegulationGenesGeneticGenomeGenomicsGoalsHenle&aposs loopHumanHuman DevelopmentHuman GeneticsHypertensionImpairmentIndividualInjuryKidneyKidney DiseasesKidney FailureKnock-in MouseKnowledgeLeadLifeMethodsModificationMolecularMusNatural regenerationNephronsNucleic Acid Regulatory SequencesNucleosomesOrganPattern FormationPhysiologicalPlayPolycombPopulationPremature BirthPremature InfantProteinsRegulationRegulatory ElementRenal functionRenal glomerular diseaseResearchRoleSignal PathwaySignal TransductionSodium ChlorideSucroseSyndromeTestingTimeTissuesTranslatingTubular formationUndifferentiatedWNT Signaling PathwayWaterWorkcell typeconditional mutantend-stage organ failureepigenomicsexhaustiongene regulatory networkgenome-widehuman diseaseinduced pluripotent stem cellinhibitorinsightkidney cellmutantnephrogenesisnephron progenitornovelpredictive modelingprogenitorpromoterrenal epitheliumrepairedself-renewalstem cell growthstem cell proliferationstem cellstranscription factor
项目摘要
The long-term goal of the proposed work is to determine mechanisms that control gene regulatory networks
to generate a normal endowment of mature nephrons. Formation of the proper complement of nephrons
requires a balance between self-renewal and differentiation of progenitor cells. Disruption of this balance leads
to renal hypoplasia and chronic kidney disease. Soon after progenitor cells begin to differentiate, chromatin
must undergo significant changes to set up gene expression patterns for formation of distinct cell types along
the nephron. Defects in formation of specific renal epithelial cell types leads to glomerular disease and an
inability of tubules to perform normal physiological functions, such as maintaining salt and water balance.
A major mechanism by which cells respond to signals to direct gene expression to a particular fate or
lineage is through the concerted action of chromatin remodeling complexes and tissue restricted transcription
factors. These proteins act on regulatory regions in the genome to establish control of gene expression at the
correct time and place. While individual factors that control gene expression in nephron progenitor cells have
been defined, how these proteins cooperate to control gene expression in the developing kidney has not been
explored. The identification and characterization of the regulatory elements where these factors act is also a
major challenge in the field.
We discovered that Sall1 plays a pivotal role in these developmental decisions by interacting with two
distinct chromatin remodeling complexes, the Nucleosome Remodeling and Deacetylase (NuRD) complex and
the Switch/Sucrose Non-Fermentable (SWI/SNF) complex. We propose that the integrated actions of Sall1,
Six2, NuRD and SWI/SNF controls nephron progenitor cell gene expression to attain a dynamic balance
between self-renewal and differentiation, and establishes the epigenetic modifications required for formation of
specific cell lineages in the mature kidney. This novel paradigm will be tested in three Aims. In Aim 1, we will
perform Hi-ChIP to identify enhancer-promoter contacts in uncommitted and induced progenitors, and define
changes in mutant cells. Aim 2 will determine how genomic binding of Sall1, Six2, NuRD and SWI/SNF are
affected in mutant nephron progenitor cells. Epigenomic editing will be used to demonstrate causal
relationships between gene expression and binding of these factors at regulatory regions. In order to translate
our findings to human development and disease, in Aim 3 we will test our findings in the mouse from Aims 1
and 2 in human iPS cell-derived nephron progenitor cells.
These studies will illuminate mechanisms that underlie human genetic syndromes and sporadic birth
defects, such as renal hypoplasia, which commonly cause childhood kidney failure. Our findings will also
provide insight into how to reprogram kidney cells from a differentiated state back to a progenitor state, to
promote regeneration of mature tubular epithelial cells in order to correct nephron deficits.
这项工作的长期目标是确定控制基因调控网络的机制
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MICHAEL I RAUCHMAN其他文献
MICHAEL I RAUCHMAN的其他文献
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{{ truncateString('MICHAEL I RAUCHMAN', 18)}}的其他基金
Research Project 2: Molecular analysis of developing post-natal mouse kidney in health and FSGS
研究项目2:健康和FSGS中小鼠产后肾脏发育的分子分析
- 批准号:
10530271 - 财政年份:2022
- 资助金额:
$ 42.22万 - 项目类别:
Research Project 2: Molecular analysis of developing post-natal mouse kidney in health and FSGS
研究项目2:健康和FSGS中小鼠产后肾脏发育的分子分析
- 批准号:
10707966 - 财政年份:2022
- 资助金额:
$ 42.22万 - 项目类别:
Single Cell Chromatin Profiling in Kidney Tissue
肾脏组织中的单细胞染色质分析
- 批准号:
10373426 - 财政年份:2021
- 资助金额:
$ 42.22万 - 项目类别:
Epigenetic mechanisms of gene regulation in nephron progenitor cell proliferation and differentiation
肾单位祖细胞增殖和分化基因调控的表观遗传机制
- 批准号:
10289761 - 财政年份:2021
- 资助金额:
$ 42.22万 - 项目类别:
Epigenetic mechanisms of gene regulation in nephron progenitor cell proliferation and differentiation
肾单位祖细胞增殖和分化基因调控的表观遗传机制
- 批准号:
10672271 - 财政年份:2021
- 资助金额:
$ 42.22万 - 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
- 批准号:
9607382 - 财政年份:2018
- 资助金额:
$ 42.22万 - 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
- 批准号:
9258431 - 财政年份:2014
- 资助金额:
$ 42.22万 - 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
- 批准号:
8638282 - 财政年份:2014
- 资助金额:
$ 42.22万 - 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
- 批准号:
8908006 - 财政年份:2014
- 资助金额:
$ 42.22万 - 项目类别:
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