Tissue Responses to Metabolic Stress

组织对代谢应激的反应

基本信息

批准号：
9044213
负责人：
JEAN E. SCHAFFER
金额：
$ 51.28万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/9044213
关键词：
Affinity Chromatography Antioxidants Biology Boxing Cardiomyopathies Cell Death Cell Nucleolus Cells 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 programs public health relevance response social stigma stellate cell transcriptome sequencing

项目摘要

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（由适用提供）：在非酒精性脂肪肝疾病（NAFLD）中，过量的脂质积累会损害肝炎，导致脂肪性肝炎或肝硬化。鉴于NAFLD的高流行和肝功能障碍的严重后果，了解肝脏中脂毒性的发病机理对人类健康至关重要。我们最近的研究发现了在RPL13A基因座中编码的小型核RNA（SNORNA）在非脂肪组织对脂质过载的反应中的意外作用。这些非编码RNA可能通过将2ʹ'-O-甲基化靶向特定的细胞RNA来起作用，尽管尚不清楚RPL13A snornas的精确靶标。这项研究的第一个目的将通过使用两种完整的系统生物学方法来探测RPL13A snORNAS的作用机理，以在脂蛋白毒性条件下识别肝细胞中snornas的靶标。这项研究的第二个目的将利用SNORNA功能丧失的鼠模型来分析RPL13A snornas对饮食诱发的脂肪性肝炎的身体贡献。