Mechanisms of Intestinal Stem Cell Injury and Repair

肠干细胞损伤与修复机制

基本信息

批准号：
10197914
负责人：
LINDA C. SAMUELSON
金额：
$ 42.21万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-17 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197914
关键词：
Acute Adult Affect Antibodies Cell Count Cell Maintenance Cell physiology Cells Columnar Cell Enterobacteria phage P1 Cre recombinase Epithelial Epithelial Cells Exhibits Generations Genetic Genetic Models Hematopoietic Stem Cell Mobilization Homeostasis IGF1 gene Injury Insulin-Like Growth Factor I Intestinal Diseases Intestinal Mucosa Intestines Knowledge Ligands Longevity Mesenchymal Mesenchyme Modeling Mouse Strains Mucous Membrane Mus Natural regeneration Notch Signaling Pathway Paneth Cells Pathway interactions Pharmacology Radiation Injuries Recovery Regenerative response Reserve Stem Cell Role Signal Pathway Signal Transduction Spottings Testing Therapeutic Time Tissues adult stem cell base cell injury crypt cell design gamma irradiation injury and repair injury recovery intestinal crypt intestinal epithelium mouse genetics mouse model notch protein novel regenerative approach regenerative therapy regenerative tissue repaired stem cell expansion stem cell function stem cell model stem cell niche stem cell population stem cells theories tissue repair tool treatment strategy

项目摘要

PROJECT SUMMARY This new R01 application seeks to define mechanisms of intestinal mucosal repair after stem cell injury, investigating the role of two key signaling pathways Dll1/4-Notch signaling and IGF1-mTORC1 signaling for promoting crypt repair. Adult stem cells fuel the continuous renewal of the intestinal epithelium. Prevailing theory suggests that there are two stem cell populations: active stem cells (also termed crypt base columnar (CBC) cells) important for epithelial cell maintenance during homeostasis and facultative stem cells (also termed quiescent or reserve stem cells) important for replenishing CBCs during crypt recovery after injury- induced stem cell loss. Intestinal crypts exhibit remarkable plasticity, with various epithelial cells in the crypt capable of reprogramming to fill unoccupied niche spots to replenish the CBC stem cell pool. Mechanisms of crypt repair and facultative stem cell mobilization are currently poorly understood. This project aims to define key niche signals that drive the regenerative response. Two mouse models of stem cell injury will be studied, including the well-established 12 Gy gamma-irradiation model and a new model of CBC loss resulting from acute Notch inhibition that we define in this proposal. Our preliminary findings show that these two injuries both result in rapid CBC loss followed by a hyperproliferative regenerative response associated with a surge of Notch pathway signaling. Our preliminary studies also show that IGF-1 expression is induced by injury and that mTORC1 signaling is required for crypt repair. The proposed studies will: (1) identify specific Notch ligands required for the regenerative response, (2) test the role of Paneth cells in the regeneration response, and (3) test the role of IGF-1 and mTORC1 signaling for crypt repair and facultative stem cell mobilization. Furthermore, the studies will expand our knowledge of the intestinal stem cell niche, including definition of key niche cells in the epithelium and mesenchyme that respond to injury to regulate stem cell function. The studies take advantage of available genetic mouse models and pharmacologic tools to manipulate the signaling pathways under study to probe their function in adult mice. Understanding mechanisms regulating intestinal stem cell expansion and crypt regeneration is important to identify key strategies to propagate adult stem cells in culture for regenerative therapies as well as to develop treatment strategies for intestinal diseases associated with mucosal injury.

项目概要这项新的 R01 应用旨在定义干细胞损伤后肠粘膜修复的机制，研究两个关键信号通路 Dll1/4-Notch 信号传导和 IGF1-mTORC1 信号传导的作用促进隐窝修复。成体干细胞促进肠上皮的持续更新。盛行理论表明有两种干细胞群：活性干细胞（也称为隐窝基底柱状细胞）（CBC）细胞）对于稳态期间上皮细胞的维持和兼性干细胞（也称为静止干细胞或储备干细胞）对于损伤后隐窝恢复过程中补充 CBC 很重要- 诱导干细胞损失。肠隐窝表现出显着的可塑性，隐窝内有多种上皮细胞能够重新编程以填充未占据的生态位点以补充 CBC 干细胞库。机制目前对隐窝修复和兼性干细胞动员知之甚少。该项目旨在定义驱动再生反应的关键利基信号。将研究两种干细胞损伤的小鼠模型，包括完善的 12 Gy 伽马辐射模型和新的 CBC 损失模型我们在本提案中定义的急性Notch抑制。我们的初步调查结果表明，这两起伤害都导致 CBC 快速丢失，随后出现与细胞激增相关的过度增殖性再生反应 Notch 通路信号传导。我们的初步研究还表明 IGF-1 表达是由损伤诱导的，并且 mTORC1 信号传导是隐窝修复所必需的。拟议的研究将：（1）识别特定的Notch配体再生反应所需的，（2）测试潘氏细胞在再生反应中的作用，以及（3）测试 IGF-1 和 mTORC1 信号传导在隐窝修复和兼性干细胞动员中的作用。此外，这些研究将扩大我们对肠道干细胞生态位的了解，包括关键的定义上皮和间质中的生态位细胞对损伤做出反应以调节干细胞功能。研究利用现有的遗传小鼠模型和药理学工具来操纵信号传导正在研究其在成年小鼠中的功能的途径。了解肠道调节机制干细胞扩增和隐窝再生对于确定繁殖成体干细胞的关键策略非常重要用于再生疗法的培养以及开发肠道疾病的治疗策略与粘膜损伤有关。