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

禁食可保护小肠干细胞免受致命性 DNA 损伤：机制洞察和临床前转化

基本信息

批准号：
9307224
负责人：
HELEN M PIWNICA-WORMS
金额：
$ 48.29万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-14 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307224
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Acetylation Adverse effects Animals Clinical DNA Damage Disease Dose Duodenum Epigenetic Process Etoposide Exposure to FOXO3A gene Fasting Gene Expression Genes Genetic Transcription Global Change Goals Head of pancreas High Dose Chemotherapy Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Intestines Ketone Bodies Kidney LCN2 gene LGR5 gene Lead Malignant neoplasm of pancreas Metabolic Molecular Mus Production Proteins Radiation Radiation therapy Reaction Regimen Serum Small Intestines Stem cells Testing Tissues Toxic effect Translations beta-Hydroxybutyrate cell killing chemotherapy clinical application inhibitor/antagonist insight ketogenesis killings mouse model neoplastic cell novel pancreatic cancer cells pre-clinical prevent programs promoter protective effect

项目摘要

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.

项目摘要/摘要已显示短期禁食可从与高毒性相关的毒性中提供宿主保护作用剂量化疗。我们发现用短期禁食赋予的一种新颖的保护作用高剂量化疗。我们证明了24小时的禁食小鼠对小肠道（SI）赋予了保护来自高剂量依托泊苷的干细胞。我们还显示出在禁食24的小鼠中的生存率增加 h用有毒剂量的辐射治疗之前。我们将检验代谢变化的假设与禁食有关导致SI干细胞的表观遗传变化，这又导致基因表达其蛋白质产物可保护SI干细胞免受致命DNA损伤。该假设将在禁食中进行检验暴露于高剂量依托泊苷和暴露于高剂量辐射的小鼠。我们的临床应用结果将在胰腺癌的小鼠模型中进行评估。