Intestinal Stem Cell Function During Aging and Tumor Initiation

项目总结/摘要 肠上皮是一种快速自我更新的组织，其在消化道内使用不同的再生机制。 稳态和损伤诱导的修复。组织再生由异质细胞类型支持，包括 循环Lgr 5+肠干细胞（ISCs）以及为受伤时留出的储备干细胞。我们有 最近报道了Wnt途径配体在Lgr 5 + ISC维持和自我调节中的重要分子作用。 退款我们还开发了新的工具，用于ISC利基的药理学操作。而 成体干细胞用于维持和修复组织的一生，多项研究表明， 是与年龄相关的多种不同组织中干细胞再生能力的下降。我们 初步数据支持ISC的再生功能减弱，并表明这些变化是由 干细胞生态位的改变导致ISCs中Wnt信号的减少。我们假设这个年龄- 相关的生态位改变驱动了受损的ISCs再生功能，并且这些变化是可逆的。我们 通过以下具体目的来评估该假设：（1）确定间充质生态位如何有助于 衰老过程中稳态再生的功能性ISC下降和（2）检查配体水平的Wnt途径 在衰老过程中结直肠肿瘤发生的背景下进行操作。实现这些目标将提供 深入了解ISC生物学的令人兴奋的新领域，并最终导致组织修复的改进策略， 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.