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

肠道干细胞微环境扰动和损伤后区域特化、机械力和表观遗传记忆的作用

• 批准号: 10442012
• 负责人: Ophir D Klein
• 金额: $ 6.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442012
• 关键词: Abdomen; Ablation; Activities of Daily Living; Basic Science; Biological Assay; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cells; Cellular Structures; Chemicals; Chromatin; Cues; DNA Methylation; Data; Disease; Distal; Duodenum; Epigenetic Process; Epithelial; Epithelial Cells; Exposure to; Face; Feedback; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Grain; Granuloma; Health; Helminths; Homeostasis; Human; Immunofluorescence Microscopy; Impairment; Implant; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intestinal Mucosa; Intestines; Ion Channel Gating; LGR5 gene; Lead; Length; Malignant Neoplasms; Measures; Mechanics; Memory; Metabolic Diseases; Molecular; Morphology; Mus; Nematospiroides dubius; Organoids; Pathology; Pattern; Pharmacology; Piezo 1 ion channel; Piezo 2 ion channel; Population; Positioning Attribute; Process; Regenerative Medicine; Role; Shapes; Signal Transduction; Small Intestines; Techniques; Testing; Tissues; Transposase; Up-Regulation; Villus; Work; assault; epidermis cell; epigenetic memory; epithelial injury; epithelial stem cell; experience; experimental study; ileum; imaging approach; inhibitor/antagonist; intestinal epithelium; intestinal injury; irradiation; jejunum; mechanical force; regenerative tissue; repaired; response; restoration; single-cell RNA sequencing; stem cell division; stem cells; transcriptome sequencing; translational approach

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.

项目总结/摘要 小肠上皮每2 ~ 5天更新一次，是更新最快的上皮之一。 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， 每天都虽然在过去的几年里已经了解了很多关于肠道干细胞（ISCs）的知识， 燃料稳态更新，上皮感觉和响应损伤的机制很差 介绍了了解肠道对损伤的反应以及体内平衡是如何重建的， 重要的基础科学问题以及转化方法的基本出发点， 再生医学在上一轮ISC联盟（ISCC）中，我们确定了关键信号， 调节ISC，并发现损伤导致ISC微环境的重塑。在本申请中， 我们将努力实现ISCC的目标，即确定支持健康领域ISCs的最低限度的必要因素 和疾病在特定目标中，我们建议确定区域专业化，表观遗传记忆 和局部力的形状响应的扰动和损伤的隐窝微环境。