Regulatory cascades in gastrointestinal proliferation

胃肠道增殖的调节级联反应

• 批准号: 9474868
• 负责人: KLAUS H KAESTNER
• 金额: $ 39.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-20 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9474868
• 关键词: Ablation; Address; Adult; Animals; Award; Cell Differentiation process; Cell Proliferation; Cells; Cellular biology; Cessation of life; Colon; Complex; Data; Defect; Development; Diphtheria Toxin; Employee Strikes; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; FOXL1 gene; Fetal Development; Genes; Genetic; Genetic Transcription; Growth; Health; Histologic; Histones; Incidence; Intestines; Knowledge; LGR5 gene; Life; Ligands; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Modification; Molecular; Molecular Analysis; Mus; Mutant Strains Mice; Myofibroblast; Natural regeneration; Pathway interactions; Polycomb; Porcupines; Process; Proteins; Publications; Signal Pathway; Smooth Muscle Actin Staining Method; Source; Stem cells; Stomach; Suggestion; Tamoxifen; Testing; Tissues; United States; Up-Regulation; WNT Signaling Pathway; Wnt proteins; carcinogenesis; cell type; demethylation; gastrointestinal; gene repression; intestinal epithelium; mouse model; mutant; progenitor; stem cell biology; stem cell niche; tool

The intestinal epithelium is one of the most rapidly renewing tissues in the body, and thus the ideal tissue to study somatic stem and progenitor cell biology. The small intestinal epithelium is composed of a single layer of cells that contains four major differentiated cell types as well as intestinal stem cells (ISCs) and progenitor or transit amplifying cells that replenish differentiated cells throughout life. While the past twenty years have seen great progress in our understanding of the signaling pathways and transcriptional regulators that control intestinal proliferation and differentiation, our understanding of the epigenetic factors that control these important processes is rather limited. Equally important is the identification of the intestinal stem cell niche, and the characterization of its function in molecular detail. To address this knowledge gap, I propose the following Specific Aims: In specific Aim 1, we will determine if Foxl1+ subepithelial telocytes are required for providing critical Wnt signals during gastrointestinal development and in R-spondin free enteroid culture. We will employ our newly developed genetic and molecular tools to determine the signaling pathways controlled by telocytes during intestinal development using mouse models. In Aim 2, we will investigate the contribution of polycomb complex mediated gene repression via histone H3K27 trimethylation on intestinal stem cell biology and regeneration. To this end, we will employ tissue and cell type specific gene ablation of two genes encoding critical H3K27me3 demethylases in the intestinal epithelium, both under homeostatic conditions and after ablation of Lgr5 stem cells. RELEVANCE (See instructions): Gastrointestinal cancer is a significant health problem, ranking fourth in incidence and second in death among cancers in the United States. Abnormal differentiation and increased proliferation of the intestinal epithelium are hallmarks of carcinogenesis. The molecular mechanisms that regulate cellular proliferation and differentiation in gastrointestinal development are far from being understood completely. Therefore, we will analyze the impact of the intestinal stem cell niche cells on intestinal growth and function, and test the contribution of histone demethylation to intestinal health.

肠上皮细胞是体内更新最快的组织之一，因此是修复肠道的理想组织。 研究体干细胞和祖细胞生物学。小肠上皮由单层组成 包含四种主要分化细胞类型以及肠干细胞（ISCs）和祖细胞的细胞 或者是在整个生命过程中补充分化细胞的运输放大细胞。虽然过去的二十年 看到了我们对信号通路和转录调节因子的理解的巨大进步， 控制肠道增殖和分化，我们对控制肠道增殖和分化的表观遗传因素的理解 这些重要的过程相当有限。同样重要的是肠干细胞的鉴定 生态位，并在分子细节上表征其功能。为了弥补这一知识缺口，我建议 以下具体目标： 在具体目标1中，我们将确定Foxl 1+上皮下端细胞是否是提供关键Wnt所必需的。 在胃肠发育期间和在无R-脊椎蛋白的类肠培养物中的信号。我们将使用我们的 新开发的遗传和分子工具，以确定由端细胞控制的信号通路 在肠道发育过程中使用小鼠模型。在目标2中，我们将研究 多梳复合物介导的组蛋白H3 K27三甲基化对肠干细胞的基因抑制作用 生物学和再生为此，我们将采用两种组织和细胞类型特异性基因消融， 肠上皮中编码关键H3 K27 me 3去甲基化酶的基因，两者均处于稳态 条件下和消融Lgr 5干细胞后。 相关性（参见说明）： 胃肠癌是一个重大的健康问题，发病率居第四位，死亡率居第二位 在美国的癌症中。肠上皮细胞异常分化和增殖增加 上皮是癌发生的标志。调节细胞增殖的分子机制 和胃肠发育的分化还远未完全理解。所以我们 将分析肠道干细胞小生境细胞对肠道生长和功能的影响，并测试 组蛋白去甲基化对肠道健康的贡献。