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
• 负责人: Qiao Joe Zhou
• 金额: $ 53.83万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10298777
• 关键词: Adult; Appearance; Binding; Biological; Biological Assay; Biology; Cell Lineage; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Colon; Colonic Diseases; Colorectal Cancer; Competence; Data; Development; Disease; Disease susceptibility; Duodenum; Enhancers; Enterocytes; Epithelial; Excision; Failure; Fatty Liver; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Gland; Goals; Growth; Histology; Homeostasis; Immunohistochemistry; Intestinal Diseases; Intestinal permeability; Intestines; LGR5 gene; Large Intestine; Malabsorption Syndromes; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Morphology; Mosaicism; Mucous Membrane; Mus; NuRD complex; Nutrient; Paneth Cells; Phenotype; Physiological; Physiology; Play; Regulation; Role; Short Bowel Syndrome; Small Intestines; Structure; Therapeutic; Tissues; Transcriptional Activation; Transcriptional Regulation; Ulcerative Colitis; Villus; Water; Weight Gain; XCL1 gene; base; blood glucose regulation; cell type; cofactor; combat; genome-wide; ileum; inflammatory disease of the intestine; insight; jejunum; mouse model; mutant; novel therapeutic intervention; nutrient absorption; permissiveness; preservation; recruit; stem cells; therapeutic development; transcription factor; transcriptome sequencing; transcriptomics; uptake

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.

项目概要 结肠是肠道的主要部分，与小肠有显着不同 形态、细胞类型、生理功能和疾病易感性。 疾病，包括结直肠癌和溃疡性结肠炎，起源于结肠而不是小肠。 结肠吸收水分，但不能像小肠那样吸收大部分营养，因此 小肠的大量损失将导致结肠无法补偿的消化衰竭。 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。 区分结肠和小肠并控制结肠特异性细胞谱系的决定因素 分化和稳态在很大程度上仍然没有特征，阻碍了更深入的理解 在初步研究中，我们发现了 SATB2，一种具有相关性的染色质因子。 结肠上皮中的限制性表达，作为结肠身份的关键分子调节剂 成人肠道的 SATB2 缺失导致结肠的同源异型转化。 将上皮细胞变成细胞组成和基因表达类似于小肠回肠的细胞， 突变的结肠可以吸收营养，这是小肠特有的功能。 表明 SATB2 是结肠上皮的潜在“主调节因子”。 提供了一个独特的机会来研究结肠个体发育和命运决定，并评估其 在该项目中，目标 1 将评估结肠干细胞的假设。 含有引发的回肠增强子，因此对回肠具有染色质水平的许可性 Aim 2 研究将评估 SATB2 的假设。 招募两种染色质重塑因子 MTA2 和 SMARCD2，以分离结肠和 回肠增强子修饰局部染色质，允许肠道转录因子的差异访问 在目标 3 中，使用短肠综合征小鼠模型。 （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 SBS 的病理生理学。 SATB2 保留结肠特性并影响结肠到回肠的分子机制 转化，这可能被用作治疗 SBS 的一种新的治疗方法。