Intestinal Stem Cell Function During Aging and Tumor Initiation

项目摘要/摘要 肠上皮是一种快速自我更新的组织，在 动态平衡和损伤诱导的修复。组织再生受到异种细胞类型的支持，包括 循环Lgr5+肠道干细胞(ISCs)以及为受伤时预留的备用干细胞。我们有 最近报道了Wnt途径配体在Lgr5+ISC维持和自我调节中的重要分子作用 更新。我们还开发了用于ISC利基的药理操作的新工具。而当 成体干细胞用于终生维持和修复组织，多项研究表明 是与年龄相关的干细胞在多个不同组织中再生能力的下降。我们的 初步数据支持ISCs的再生功能减弱，并表明这些变化是由 干细胞区的改变导致了ISCs中Wnt信号的减少。我们假设年龄是- 相关的生态位改变导致ISCs的再生功能受损，这些变化是可逆的。我们的 通过以下具体目标对假说进行评估：(1)定义间充质生态位对 衰老过程中体内平衡再生的功能ISC下降和(2)检测配体水平的Wnt途径 衰老过程中结直肠肿瘤启动的操作。这些目标的实现将提供 洞察令人兴奋的ISC生物学新领域，并最终改进组织修复策略 衰老。

PROJECT SUMMARY/ABSTRACT The intestinal epithelium is a rapidly self-renewing tissue that uses distinct mechanisms for regeneration during homeostasis and injury-induced repair. Tissue regeneration is supported by heterogeneous cell types including cycling Lgr5+ intestinal stem cells (ISCs) as well as reserve stem cells set aside for times of injury. We have recently reported an essential molecular role for Wnt pathway ligands in Lgr5+ ISC maintenance and self- renewal. We have also developed novel tools for the pharmacological manipulation of the ISC niche. While adult stem cells serve to maintain and repair tissues for a lifetime, multiple studies have demonstrated that there is an age-related decline in the regenerative capacity of stem cells across multiple different tissues. Our preliminary data support diminished regenerative function in ISCs and suggest that these changes are driven by alterations in the stem cell niche that result in decreased Wnt signaling in the ISCs. We hypothesize that age- related niche alterations drive the impaired regenerative function of ISCs and these changes are reversible. Our hypothesis is evaluated by the following Specific Aims: (1) to define how the mesenchymal niche contributes to functional ISC decline in homeostatic regeneration during aging and (2) to examine ligand-level Wnt pathway manipulation in the context of colorectal tumor initiation during aging. Achievement of these Aims will provide insight into exciting new areas of ISC biology, and ultimately lead to improved strategies for tissue repair during aging.