权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of methylation-dependent pathways in aging and stress

甲基化依赖性途径在衰老和压力中的作用

基本信息

批准号：
10172812
负责人：
Amy Karol Walker
金额：
$ 40.52万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2017-09-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172812
关键词：
Address Affect Aging Animals Attenuated Biological Assay Caenorhabditis elegans Calories Cell physiology Cells Chromatin Cystic Fibrosis Defect Diet Diet Modification Disease Disease model Drug Metabolic Detoxication Epigenetic Process Escherichia coli Failure Fatty Liver Fatty acid glycerol esters Folic Acid Gene Activation Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Transcription Guanosine Triphosphate Phosphohydrolases HMGB1 Protein Histones Immune Immune response Immune signaling Immune system Immunity Immunologic Markers Laboratories Lecithin Link Lipids Liver diseases Mediating Membrane Metabolic Metabolism Methylation Methyltransferase Mitogen-Activated Protein Kinases Modeling Molecular Mutation Natural Immunity Nutrient Pathogenicity Pathway interactions Phenotype Phospholipids Phosphorylation Physiological Physiology Process Production Pseudomonas Pseudomonas aeruginosa RNA interference screen Regulation Reporter Role S-Adenosylmethionine SRE-1 binding protein Signal Pathway Signal Transduction Sphingomyelins Stimulus Stress System Techniques Transcriptional Regulation Up-Regulation Vitamin B 12 Walkers Work activating transcription factor biological adaptation to stress chromatin modification deep sequencing dietary histone methylation histone methyltransferase histone modification immune activation innate immune function insight lipidomics p38 Mitogen Activated Protein Kinase pathogen response transcriptome sequencing whole genome

项目摘要

Diet and metabolism can affect how our bodies work in many ways, not just by turning excess calories into fat. Some metabolites act as signals or can be used to modify how genes are expressed, which can link diet to how our cells function and their capacity to respond to stress. We propose to study how one metabolite, s-adenosylmethionine (SAM), can both activate markers of immunity and limit how cells can change gene expression patterns in response to pathogens or other stress. These seemingly paradoxical functions occur because SAM can be used for different cellular needs. SAM can be used to make the phospholipid phosphatidylcholine (PC) and when PC is limited by the diet or needed for extra membrane production, much of the SAM is used for this biosynthetic process. However, SAM is also needed for modification of histones. Using C. elegans, we found that low SAM acted through low PC to activate markers of innate immunity on the standard laboratory diet. However, these same animals could not survive a bacterial challenge because they couldn't methylate histones priming gene activation and turn up pathogen responsive genes to sufficient levels. Thus, different contexts can change the phenotypes of low SAM, as cells need to prioritize utilization of this metabolite. Our proposal addresses several key questions. First, it is not known how the low SAM and PC signal activation of the immune system. Second, it is not understood how global chromatin modification under stress might change in low SAM and third, we don't yet understand how physiological regulators of low SAM might affect either of these phenotypes. Our C. elegans system is an excellent model for dissecting these mechanisms. We will combine genetic and molecular techniques (including whole genome assays for chromatin modification) with dietary modification to determine how SAM is linked to these phenotypes. We have used screens for SAM and PC-dependent modifiers of immunity to identify additional regulatory components and propose to determine how these candidates may be connected to immune activation. Furthermore, we have determined that multiple types of stress-induced gene expression depend on SAM and will use this system to ask how SAM and the histone methyltransferases utilizing it control transcription during stress. Although low SAM can cause phenotypes with very distinct molecular mechanisms, such as lipid-dependent activation of a MAP kinase in the immune response and modification of histones in transcriptional regulation, it is important to study these processes together. SAM depletion due to diet may impact either or both of these mechanisms, changing how our cells can respond to stress.

饮食和新陈代谢可以在很多方面影响我们身体的工作方式，而不仅仅是通过转化过剩