Regulatory cascades in gastrointestinal proliferation

肠上皮是体内更新最快的组织之一，因此是理想的组织 研究体细胞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 (ISC) 和祖细胞的细胞 或转运放大细胞，在整个生命过程中补充分化细胞。虽然过去二十年 我们对信号通路和转录调节因子的理解取得了巨大进展 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。同样重要的是肠道干细胞的鉴定 利基，及其分子细节功能的表征。为了解决这一知识差距，我建议 具体目标如下： 在具体目标 1 中，我们将确定 Foxl1 上皮下特细胞是否需要提供关键的 Wnt 胃肠道发育期间和无 R-spondin 肠样培养物中的信号。我们将雇用我们的 新开发的遗传和分子工具来确定特细胞控制的信号通路 使用小鼠模型进行肠道发育期间。在目标 2 中，我们将调查 多梳复合物通过组蛋白 H3K27 三甲基化介导肠干细胞基因抑制 生物学和再生。为此，我们将采用组织和细胞类型特异性基因消融两种 肠上皮中编码关键 H3K27me3 去甲基酶的基因，均处于稳态状态 条件和 Lgr5 干细胞消融后。 相关性（参见说明）： 胃肠癌是一个严重的健康问题，发病率排名第四，死亡人数排名第二 在美国的癌症中。肠道分化异常和增殖增加 上皮细胞是癌发生的标志。调节细胞增殖的分子机制 胃肠道发育的差异和分化还远未完全了解。因此，我们 将分析肠道干细胞生态位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。

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.