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.

肠上皮是体内更新最快的组织之一，因此是 研究体细胞干细胞和祖细胞生物学。小肠上皮由单层构成。 包含四种主要分化细胞类型的细胞以及肠道干细胞(ISCs)和祖细胞 或者运输放大细胞，在一生中补充分化的细胞。而在过去的二十年里 在我们对信号通路和转录调控因子的理解方面取得了很大进展 控制肠道增殖和分化，我们对控制表观遗传因素的理解 这些重要的进程相当有限。同样重要的是肠道干细胞的鉴定。 生态位，以及其功能的分子细节表征。为了解决这一知识鸿沟，我建议 以下是具体目标： 在特定的目标1中，我们将确定是否需要Foxl1+上皮下端粒细胞来提供关键的Wnt 在胃肠道发育和无R-响应素的肠样培养中的信号。我们将雇佣我们的员工 新开发的基因和分子工具来确定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，我们将调查以下方面的贡献 组蛋白H3K27三甲基化介导的多梳复合体对肠干细胞的基因抑制 生物学和再生。为此，我们将采用组织和细胞类型特异的基因消融两种 肠上皮中编码关键H3K27me3去甲基酶的基因，两者都处于动态平衡状态 Lgr5干细胞的培养条件和消融后。 相关性(请参阅说明)： 胃肠道癌症是一个重大的健康问题，发病率排名第四，死亡率排名第二。 在美国的癌症中。肠道分化异常和增殖增加 上皮细胞是癌变的标志。调控细胞增殖的分子机制 而胃肠道发育过程中的分化还远未完全了解。因此，我们 将分析肠道干细胞巢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。