The roles of regional specialization, mechanical forces and epigenetic memory after perturbation and injury of the intestinal stem cell microenvironment

项目摘要/摘要 小肠上皮每2至5天更新一次，使其成为更新最快的 哺乳动物体内的组织。这种高度再生的组织面临着大量的侮辱和伤害 按天算。虽然在过去的几年里，关于肠道干细胞(ISCs)的研究已经很多，但 促进动态平衡更新，上皮细胞对损伤的感知和反应机制很差 描述。了解肠道如何对侮辱做出反应以及如何重建内环境平衡 重要的基础科学问题以及翻译方法的基本起点 再生医学。在上一轮ISC联盟(ISCC)中，我们确定了关键信号 对间质干细胞进行调控，发现损伤导致间质干细胞微环境重塑。在此应用程序中， 我们将朝着ISCC的目标努力，即确定支持ISCs健康的最低限度的必要因素 和疾病。在具体目标上，我们建议确定区域专门化、表观遗传记忆 局部作用力塑造了对隐窝微环境中的扰动和损伤的反应。

PROJECT SUMMARY/ABSTRACT The epithelium of the small intestine renews every 2 to 5 days, making it one of the most rapidly renewing tissues in the mammalian body. This highly regenerative tissue faces a multitude of insults and injuries on a daily basis. While much has been learned over the past few years about the intestinal stem cells (ISCs) that fuel homeostatic renewal, the mechanisms by which the epithelium senses and responds to damage are poorly described. Understanding how the intestine reacts to insults and how homeostasis is reestablished are important basic science questions as well as essential starting points for translational approaches in regenerative medicine. In the previous round of the ISC Consortium (ISCC), we identified critical signals that regulate ISCs and discovered that injury leads to remodeling of the ISC microenvironment. In this application, we will work toward the ISCC goal of characterizing the minimal, required factors that support ISCs in health and disease. In the Specific Aims, we propose to determine how regional specialization, epigenetic memory and local forces shape responses to perturbation and injury in the crypt microenvironment.