Investigating a master regulator of large intestine stem cells
研究大肠干细胞的主调节因子
基本信息
- 批准号:10458677
- 负责人:
- 金额:$ 50.73万
- 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:2021-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAppearanceBindingBiologicalBiological AssayBiologyCell LineageCellsChIP-seqChromatinChromatin Remodeling FactorColonColonic DiseasesColorectal CancerCompetenceDataDevelopmentDiseaseDisease susceptibilityDuodenumEnhancersEnterocytesEpithelialExcisionFailureFatty LiverFunctional disorderGene ExpressionGenesGeneticGenetic TranscriptionGlandGoalsGrowthHistologyHomeostasisImmunohistochemistryIntestinal DiseasesIntestinal permeabilityIntestinesLGR5 geneLarge IntestineMalabsorption SyndromesMass Spectrum AnalysisMediatingModelingMolecularMorphologyMosaicismMucous MembraneMusNuRD complexNutrientPaneth CellsPhenotypePhysiologicalPhysiologyPlayRegulationRoleShort Bowel SyndromeSmall IntestinesStructureTherapeuticTissuesTranscriptional ActivationTranscriptional RegulationUlcerative ColitisVillusWaterWeight GainXCL1 genebaseblood glucose regulationcell typecofactorcombatgenome-widegut inflammationileuminsightjejunummouse modelmutantnovel therapeutic interventionnutrient absorptionpermissivenesspreservationrecruitstem cellstherapeutic developmenttranscription factortranscriptome sequencingtranscriptomicsuptake
项目摘要
PROJECT SUMMARY
The colon is a major segment of the intestine and differs significantly from the small intestine in
morphology, cell types, physiological function and disease susceptibility. Devastating and prevalent
diseases, including colorectal cancers and ulcerative colitis, arise from colon but not small intestine.
Colon absorbs water but cannot uptake most nutrients like the small intestine and consequently a
significant loss of the small intestine will lead to digestive failure that the colon cannot compensate.
Despite significant progress, aspects of the colon biology remain poorly understood. Molecular
determinants that distinguish the colon from the small intestine and govern colon-specific cell lineage
differentiation and homeostasis remain largely uncharacterized, hindering a deeper understanding of
regionalized intestinal diseases. In preliminary studies, we identified SATB2, a chromatin factor with
restricted expression in the colonic epithelium, as a crucial molecular regulator of colon identity and
differentiation. SATB2 deletion from adult intestine led to a homeotic-like transformation of colonic
epithelium into one that resembles small intestine ileum in cellular composition and gene expression,
and the mutant colon can absorb nutrients, a function unique to the small intestine. These data
suggest that SATB2 is a potential “master regulator” of colonic epithelium. The identification of SATB2
offers a unique opportunity to study colonic ontogeny and fate determination, and assess its
therapeutic implications. In this project, Aim 1 will evaluate the hypothesis that colonic stem cells
harbor primed ileal enhancers and thus harbor a chromatin-level permissiveness for ileal
transcriptional activation and cell fate plasticity. Aim 2 studies will evaluate the hypothesis that SATB2
recruits two chromatin remodeling factors, MTA2 and SMARCD2, to separate pools of colonic and
ileal enhancers to modify local chromatin, allowing differential access of intestinal transcription factors
and effecting transcriptional regulation. In Aim 3, using mouse models of Short bowel syndrome
(SBS), we will evaluate whether promoting colonic nutrient absorption can combat digestive failure
and the associated pathophysiology in SBS. These studies together will elucidate the cellular and
molecular mechanisms by which SATB2 preserves colonic identity and effects a colonic to ileal
conversion, which may be exploited as a novel therapeutic approach to treat SBS.
项目摘要
结肠是肠道的主要部分,在以下方面与小肠显著不同:
形态、细胞类型、生理功能和疾病易感性。破坏性和普遍性
包括结肠直肠癌和溃疡性结肠炎在内的疾病是由结肠而不是小肠引起的。
结肠吸收水分,但不能像小肠那样吸收大多数营养物质,
小肠的显著损失将导致结肠不能补偿的消化衰竭。
尽管取得了重大进展,但对结肠生物学的各个方面仍然知之甚少。分子
区分结肠和小肠并控制结肠特异性细胞谱系的决定因素
分化和内稳态仍然在很大程度上没有特征,阻碍了更深入地了解
区域性肠道疾病在初步研究中,我们鉴定了SATB 2,一种染色质因子,
在结肠上皮中的限制性表达,作为结肠特性的关键分子调节剂,
分化SATB 2从成年人肠道中缺失导致结肠癌的同源异型转化,
在细胞组成和基因表达方面类似于小肠回肠,
变异的结肠可以吸收营养,这是小肠特有的功能。这些数据
表明SATB 2是结肠上皮潜在“主调节因子”。SATB 2的鉴定
提供了一个独特的机会,研究结肠个体发育和命运的决定,并评估其
治疗意义在这个项目中,目标1将评估结肠干细胞
含有引发的回肠增强子,因此含有对回肠的染色质水平的容许性,
转录激活和细胞命运可塑性。目标2研究将评估SATB 2
招募了两种染色质重塑因子,MTA 2和SMARD 2,以分离结肠和结肠癌细胞的库。
回肠增强子修饰局部染色质,允许肠转录因子的差异进入
并影响转录调控。在目标3中,使用短肠综合征的小鼠模型,
(SBS),我们将评估促进结肠营养吸收是否可以对抗消化衰竭
以及SBS的相关病理生理学。这些研究将共同阐明细胞和
SATB 2保留结肠特性并影响结肠到回肠的分子机制
转换,这可能被开发作为一种新的治疗方法来治疗SBS。
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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Qiao Joe Zhou的其他文献
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{{ truncateString('Qiao Joe Zhou', 18)}}的其他基金
Engineering islet-like organoids from gastric stem cells for T1D cell replacement therapy
从胃干细胞中改造胰岛样类器官,用于 T1D 细胞替代疗法
- 批准号:
10704110 - 财政年份:2022
- 资助金额:
$ 50.73万 - 项目类别:
Derivation of pancreatic islet-like organoids from human gastric stem cells
从人胃干细胞中衍生胰岛样类器官
- 批准号:
10502451 - 财政年份:2022
- 资助金额:
$ 50.73万 - 项目类别:
Derivation of pancreatic islet-like organoids from human gastric stem cells
从人胃干细胞中衍生胰岛样类器官
- 批准号:
10689788 - 财政年份:2022
- 资助金额:
$ 50.73万 - 项目类别:
Engineering islet-like organoids from gastric stem cells for T1D cell replacement therapy
从胃干细胞中改造胰岛样类器官,用于 T1D 细胞替代疗法
- 批准号:
10512923 - 财政年份:2022
- 资助金额:
$ 50.73万 - 项目类别:
Investigating a master regulator of large intestine stem cells
研究大肠干细胞的主调节因子
- 批准号:
10298777 - 财政年份:2021
- 资助金额:
$ 50.73万 - 项目类别:
Investigating a master regulator of large intestine stem cells
研究大肠干细胞的主调节因子
- 批准号:
10671584 - 财政年份:2021
- 资助金额:
$ 50.73万 - 项目类别:
Generating novel sources of functional human insulin-secreting cells for T1D modeling
为 T1D 建模生成功能性人胰岛素分泌细胞的新来源
- 批准号:
9459621 - 财政年份:2017
- 资助金额:
$ 50.73万 - 项目类别:
Generating novel sources of functional human insulin-secreting cells for T1D modeling
为 T1D 建模生成功能性人胰岛素分泌细胞的新来源
- 批准号:
9849886 - 财政年份:2017
- 资助金额:
$ 50.73万 - 项目类别:
Reprogram gastric tissue to functional insulin-secreting cells
将胃组织重新编程为功能性胰岛素分泌细胞
- 批准号:
9916632 - 财政年份:2016
- 资助金额:
$ 50.73万 - 项目类别:
Reprogram gastric tissue to functional insulin-secreting cells
将胃组织重新编程为功能性胰岛素分泌细胞
- 批准号:
9221317 - 财政年份:2016
- 资助金额:
$ 50.73万 - 项目类别:
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