Fasting Protects Small Intestinal Stem Cells from Lethal DNA Damage: Mechanistic Insight and Preclinical Translation

项目摘要/摘要 短期禁食已被证明可提供宿主保护作用，免受与高血糖相关的毒性。 剂量化疗。我们发现，短期禁食对小鼠有一种新的保护作用。 大剂量化疗。我们证明了禁食24小时的小鼠对小肠(SI)具有保护作用。 来自高剂量依托泊苷的干细胞。我们还发现禁食24年的小鼠存活率增加。 在接受毒性剂量的放射治疗前的h。我们将测试代谢变化的假设 禁食导致SI干细胞的表观遗传学变化，进而导致基因表达 其蛋白质产品保护SI干细胞免受致命的DNA损伤。这一假设将在FASED中得到验证 暴露于高剂量依托泊苷的小鼠和暴露于高剂量辐射的小鼠。本品的临床应用 这些发现将在胰腺癌的小鼠模型中进行评估。

Project Summary/Abstract Short-term fasting has been shown to provide host protective effects from the toxicity associated with high- dose chemotherapy. We found a novel protective effect conferred by short-term fasting when treating mice with high dose chemotherapy. We demonstrated that fasting mice for 24 h confers protection to small intestinal (SI) stem cells from high-dose etoposide. We also showed increased survival in mice that have been fasted for 24 h prior to treatment with toxic doses of radiation. We will test the hypothesis that the metabolic changes associated with fasting lead to epigenetic changes in SI stem cells, which in turn, leads to expression of genes whose protein products protect SI stem cells from lethal DNA damage. This hypothesis will be tested in fasted mice exposed to high-dose etoposide and mice exposed to high-dose radiation. The clinical applications of our findings will be evaluated in a mouse model of pancreatic cancer.