Tissue Responses to Metabolic Stress

 描述（由申请人提供）：在非酒精性脂肪性肝病（NAFLD）中，过量脂质蓄积可损伤肝组织，导致脂肪性肝炎或肝硬化。鉴于NAFLD的高患病率和肝功能障碍的严重后果，了解肝脏中脂毒性的发病机制对人类健康至关重要。我们最近的研究揭示了一个意想不到的作用，小核仁RNA（snoRNA）编码的rpL 13 a基因座的非脂肪组织的脂质过载的反应。这些非编码RNA可能通过将2 ′-O-甲基化靶向特定的细胞RNA发挥作用，尽管脂毒性反应中rpL 13 a snoRNA的精确靶点尚不清楚。本研究的第一个目的是通过使用两种互补的系统生物学方法来确定脂毒性条件下肝细胞中snoRNA的靶点，从而探索rpL 13 a snoRNA的作用机制。本研究的第二个目的是利用snoRNA功能丧失的小鼠模型来分析rpL 13 a snoRNA对饮食诱导的脂肪性肝炎的生理贡献。

 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.