Mechanisms of fasting-induced radioprotection of small intestinal epithelial cells

禁食诱导的小肠上皮细胞辐射防护机制

• 批准号: 10645872
• 负责人: HELEN M PIWNICA-WORMS
• 金额: $ 66.15万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645872
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Animals; Automobile Driving; Bacteria; Cancer Patient; Cell Separation; Cells; ChIP-seq; Chromatin; Clinical; Coenzyme A; Data; Dose; Enhancers; Epigenetic Process; Epithelial Cells; Fasting; Gene Expression; Genes; Genetic Transcription; Goals; HDAC4 gene; Histone H3; Histone H4; Intestines; Ionizing radiation; Ketone Bodies; Knock-out; Lysine; Malignant neoplasm of pancreas; Mediating; Metabolic; Mus; Normal tissue morphology; Organ; Outcome; Patients; Probiotics; Production; Quality of life; Radiation; Radiation Dose Unit; Radiation Protection; Radiation Toxicity; Radiation induced damage; Radiation therapy; Reaction; Regimen; Resolution; Small Intestinal Goblet Cell; Small Intestines; Testing; Toxic effect; beta-Hydroxybutyrate; cell killing; epigenome; epigenomics; experimental study; gastrointestinal; gut microbiome; improved; insight; intestinal crypt; intestinal homeostasis; ketogenesis; microbial; microbiome alteration; mimetics; mouse model; neoplastic cell; novel; pancreas radiation therapy; preservation; programs; promoter; protective effect; radioprotected; repaired; response; side effect; single cell analysis; stem cells; transcriptome sequencing

Project Summary We demonstrated that short-term fasting protects mice from high dose ionizing radiation by protecting small intestinal (SI) stem cells, thereby preserving SI homeostasis and promoting organismal survival. We also showed that the major ketone body produced by fasting directly modifies the epigenome of SI epithelial cells to induce gene expression changes and that fasting alters the gut microbiome to favor bacteria whose metabolites are known to induce epigenetic and gene expression changes. We will test the hypothesis that ketone bodies and microbial metabolites induced by fasting, cause epigenetic and gene expression changes in SI epithelial cells thereby providing GI radioprotection.

项目概要 我们证明，短期禁食可以通过保护小小鼠免受高剂量电离辐射的侵害。 肠道 (SI) 干细胞，从而保持 SI 稳态并促进有机体存活。我们也 研究表明，禁食产生的主要酮体直接修饰 SI 上皮细胞的表观基因组， 诱导基因表达变化，并且禁食会改变肠道微生物群，以利于细菌的生长 已知代谢物会诱导表观遗传和基因表达变化。我们将检验以下假设： 禁食诱导的酮体和微生物代谢物，导致表观遗传和基因表达变化 SI上皮细胞从而提供GI辐射防护。