Tissue Responses to Metabolic Stress

组织对代谢应激的反应

• 批准号: 9204834
• 负责人: JEAN E. SCHAFFER
• 金额: $ 50.42万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204834
• 关键词: Affinity Chromatography; Antioxidants; Biology; Cardiomyopathies; Cell Death; Cell Nucleolus; Chemicals; Cirrhosis; Complex; Complication; Cytoplasm; Cytosol; Diabetes Mellitus; Diet; Epigenetic Process; Fatty acid glycerol esters; Fibroblasts; Fructose; Gene Expression; Genes; Health; Hepatic Tissue; Hepatocyte; High Prevalence; Human; Hydrogen Peroxide; Infiltration; Injury; Introns; Knock-in; Laboratories; Lead; Lipids; Liver; Liver Dysfunction; Liver diseases; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic stress; Metabolic syndrome; Metabolism; Methylation; Methyltransferase; Modeling; Modification; Myeloid Cells; Obesity; Oxidative Stress; Pathogenesis; Pathway interactions; Pattern; Physiological; Prevention; Process; Proteins; RNA; RNA Splicing; Reactive Oxygen Species; Ribosomal Proteins; Ribosomal RNA; Role; Small Nucleolar RNA; Small RNA; Steatohepatitis; Systems Biology; Testing; Tissues; Toxic effect; Trans Fats; Transducers; Translations; Untranslated RNA; biological adaptation to stress; cell type; defined contribution; fibrillarin; gain of function; in vivo; insight; liver injury; loss of function; mRNA Precursor; mouse model; new therapeutic target; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; oxidative damage; programs; public health relevance; response; stellate cell; transcriptome sequencing

 DESCRIPTION (provided by applicant): In non-alcoholic fatty liver disease (NAFLD), excess lipid accumulation can damage hepatic tissues leading to steatohepatitis or cirrhosis. Given the high prevalence of NAFLD and the serious consequences of liver dysfunction, understanding the pathogenesis of lipotoxicity in the liver is of high importance to human health. Our recent studies uncovered an unanticipated role for small nucleolar RNAs (snoRNAs) encoded in the rpL13a locus in the response of non-adipose tissues to lipid overload. These non-coding RNAs likely function by targeting 2ʹ′-O-methylations to specific cellular RNAs, although the precise targets of rpL13a snoRNAs in lipotoxic responses are not known. The first aim of this study will probe the mechanism of action of the rpL13a snoRNAs by using two complementary systems biology approaches to identify the targets of the snoRNAs in hepatocytes under lipotoxic conditions. The second aim of this study will leverage snoRNA loss-of-function murine models to analyze the physiological contributions of the rpL13a snoRNAs to diet-induced steatohepatitis.

 描述(申请人提供)：在非酒精性脂肪性肝病(NAFLD)中，过多的脂肪堆积会损害肝脏组织，导致脂肪性肝炎或肝硬变。鉴于NAFLD的高患病率和肝功能障碍的严重后果，了解肝脏脂肪毒性的发病机制对人类健康具有非常重要的意义。我们最近的研究发现，编码在rpL13a基因座上的小核仁RNA(SnoRNAs)在非脂肪组织对脂质超载的反应中扮演了一个意想不到的角色。这些非编码RNA可能通过靶向特定细胞RNA的2ʹ‘-O-甲基化来发挥作用，尽管rpL13a snoRNAs在脂毒反应中的确切靶点尚不清楚。本研究的第一个目的是通过两种互补的系统生物学方法来探讨rpL13a snoRNAs的作用机制，以确定在脂毒条件下肝细胞中snoRNAs的靶点。这项研究的第二个目的将利用snoRNA功能丧失的小鼠模型来分析rpL13a snoRNAs在饮食诱导的脂肪性肝炎中的生理贡献。