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：
10090461
负责人：
HELEN M PIWNICA-WORMS
金额：
$ 46.38万
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/10090461
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Acetylation Animals Chemotherapy and/or radiation 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 Dose Unit Radiation therapy Reaction Regimen Serum Small Intestines Testing Tissues Toxic effect Translations advanced pancreatic cancer beta-Hydroxybutyrate cell killing chemotherapy clinical application inhibitor/antagonist insight ketogenesis mouse model neoplastic cell novel pancreatic cancer cells pancreatic cancer model pre-clinical prevent programs promoter protective effect side effect stem cells

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.

项目概要/摘要短期禁食已被证明可以为宿主提供保护作用，使其免受与高剂量相关的毒性的影响。剂量化疗。我们发现，在用药物治疗小鼠时，短期禁食具有一种新的保护作用。高剂量化疗。我们证明，禁食 24 小时的小鼠可以保护小肠 (SI) 来自高剂量依托泊苷的干细胞。我们还发现禁食 24 小时的小鼠的存活率有所提高在接受有毒剂量的辐射治疗之前小时。我们将检验代谢变化的假设禁食会导致 SI 干细胞发生表观遗传变化，进而导致基因表达其蛋白质产品可保护 SI 干细胞免受致命的 DNA 损伤。这个假设将在禁食中得到检验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。我们的临床应用研究结果将在胰腺癌小鼠模型中进行评估。