Understanding the Mechanisms of Age-Dependent Decline of Intestinal Stem Cell Function

了解肠道干细胞功能随年龄下降的机制

• 批准号: 9385401
• 负责人: Maria M. Mihaylova
• 金额: $ 11.22万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385401
• 关键词: Ablation; Address; Adult; Affect; Age; Aging; Agonist; Animals; Area; Award; Biochemical; Biological Assay; CRISPR/Cas technology; Caloric Restriction; Carnitine O-Palmitoyltransferase; Cell Count; Cell physiology; Cellular Metabolic Process; Development; Development Plans; Diet; Dietary Intervention; Digestive System Disorders; Elderly; Environment; Enzymes; Fasting; Frequencies; Future; Gene Family; Genes; Genetic; Genetic Transcription; Genus Hippocampus; Glucose; Goals; Health; Impairment; Infection; Inflammasome; Inflammation; Institution; Intestines; Knowledge; LGR5 gene; Label; Life; Literature; Long-Term Effects; Malabsorption Syndromes; Mediating; Mentors; Metabolic; Metabolism; Molecular; Monitor; Mus; Natural regeneration; Nuclear Family; Nuclear Receptors; Organoids; PPAR alpha; PPAR delta; Palmitates; Pathologic; Pathway interactions; Pharmacology; Phase; Physiology; Play; Population; Radiation; Recovery; Recruitment Activity; Regulation; Reporter; Reporting; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Site; Starvation; Stem cells; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcriptional Regulation; Universities; VP 16; Work; absorption; adult stem cell; age related; aged; aging population; base; career development; cell age; cell type; chemotherapy; delta opioid receptor; detection of nutrient; epigenetic regulation; experimental study; fatty acid metabolism; fatty acid oxidation; functional decline; gene function; gut microbiota; improved; intestinal epithelium; intestinal homeostasis; loss of function; meetings; metabolomics; microbiome; microbiota; mitochondrial metabolism; mouse model; overexpression; programs; regenerative; response; stem cell biology; stem cell division; tissue repair; transcriptome sequencing

7. Project Summary/ Abstract A number of mammalian tissues possess regenerative capacity and rely on tissue-specific somatic stem cells cells for renewal. A fundamental question in the aging field is whether there is a functional decline in somatic stem cells with age and whether we can use dietary or therapeutic interventions to decelerate or reverse age-dependent decline of adult stem cell function. In this proposal, we seek to answer these questions using the mammalian intestine, which undergoes age-dependent functional decline and regenerates through pools of Lgr5+ intestinal stem cells (ISC). In preliminary studies we found that: 1) aged crypts have both decreased function and frequency of ISCs; 2) short-term starvation enhanced the capacity of organoid formation from aged crypts and induced strongly a Peroxisome Proliferator-Activated Receptor Delta program in the ISCs; 3) we can recapitulate fasting effects with the highly specific PPARδ agonist GW501516. In Aim 1 we will use mouse genetics to determine the necessity and sufficiency of PPARδ signaling in mediating the effects of fasting in intestinal stem cells. In Aim 2 we will utilize LC-MS and Seahorse metabolic assays to determine if mitochondrial metabolism is augmented in aged ICSs. We will also determine if CPT1A mediates augmented ISC function in the fasted state. In the independent phase and Aim3, I will examine the interplay of diet, aging and microbiota by characterizing the function and regulation of the Gasdermin C family of genes in transit-amplifying progenitor (TA) cells.

7. 项目摘要/摘要