Intestinal Stem Cell Function During Aging and Tumor Initiation

衰老和肿瘤发生过程中肠道干细胞的功能

• 批准号: 10339113
• 负责人: Kelley Yan
• 金额: $ 1.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339113
• 关键词: Aging; Cell Maintenance; Data; Homeostasis; Impairment; Injury; Intestines; LGR5 gene; Ligands; Molecular; Natural regeneration; Pathway interactions; Pharmacology; Regenerative capacity; Reporting; Reserve Stem Cell; Role; Time; Tissues; WNT Signaling Pathway; adult stem cell; age related; cell type; intestinal epithelium; novel; parent grant; regeneration function; repaired; self-renewal; stem cell function; stem cell niche; stem cells; tissue regeneration; tissue repair; tool; tumor initiation; tumorigenesis

SUMMARY 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.

摘要 肠上皮是一种快速自我更新的组织，它使用不同的再生机制。 在动态平衡和损伤诱导的修复期间。异种细胞支持组织再生 类型包括循环Lgr5+肠道干细胞(ISCs)以及为 受伤次数。我们最近报道了Wnt途径配体在Lgr5+中的一个重要分子作用 ISC维护和自我更新。我们还开发了用于药理学研究的新工具 操纵ISC利基市场。虽然成体干细胞可以终生维持和修复组织， 多项研究表明，与年龄相关的再生能力下降 干细胞跨越多个不同的组织。我们的初步数据支持减少了再生性 在ISCs中的功能，并表明这些变化是由干细胞利基的改变驱动的 导致ISCs中Wnt信号的减少。我们假设与年龄相关的生态位变化会推动 ISCs的再生功能受损，这些变化是可逆的。