Regulation of Liver Growth and Function

描述（由申请方提供）：糖尿病和肥胖是主要流行病，分别影响超过5-8%和20-25%的美国人口，是代谢失调的表现。这些疾病中显著涉及的组织是肝脏，其必须快速适应大量营养素可用性的大变化以及合成代谢和分解代谢激素的相关波动，以便与身体的其他组织协调作用以维持代谢稳态。肝脏对营养素流入或营养素缺乏的适应是通过转录、翻译和翻译后机制介导的多种生化过程来实现的。其中，目前对翻译机制知之甚少，即，将mRNA翻译成蛋白质的过程，PI实验室的专业知识是公认的研究领域。因此，拟议项目的总体目标是了解肝脏中的翻译控制机制以及调节它们的信号通路如何响应大量营养素和激素胰岛素和胰高血糖素的变化，并在此过程中为设计涉及代谢失调的疾病的治疗策略提供见解。有待检验的一般假设是，营养素和激素激活肝脏中不同和冗余的细胞信号传导途径，从而改变介导mRNA翻译调节的分子机制，这一过程有助于高度协调的基因表达模式，以响应各种生理条件下组织上代谢需求的波动。为了验证这一假设，我们提出了以下具体目标：（1）确定负责介导胰高血糖素抑制作用以及游离脂肪酸和支链氨基酸亮氨酸通过哺乳动物雷帕霉素靶蛋白（mTOR）途径激活信号传导以产生基因表达的翻译控制变化的机制;（2）鉴定负责响应于氨基酸失衡或非生理性低或高葡萄糖浓度而产生基因表达的翻译控制变化的机制和信号通路;和（3）鉴定分子机制、信号通路以及营养和激素输入，通过这些输入，白蛋白mRNA的翻译响应于食物摄入而被去抑制。我们期望在肝脏导致代谢失调的情况下确定新的治疗干预靶点。

DESCRIPTION (provided by applicant): Diabetes mellitus and obesity, major epidemics that affect more than 5-8% and 20-25% of the US population, respectively, are manifestations of dysregulated metabolism. A tissue prominently involved in these disorders is the liver which must adapt rapidly to large variations in macronutrient availability and the associated fluctuations in anabolic and catabolic hormones in order to act in coordination with other tissues of the body to maintain metabolic homeostasis. Adaptation by the liver to either an influx of nutrients or nutrient deprivation is accomplished by multiple biochemical processes mediated by transcriptional, translational, and posttranslational mechanisms. Of these, the least is presently known about translational mechanisms, i.e., the process of translating mRNA into protein, an area of research in which the expertise of the PI's laboratory is well-recognized. Therefore, the overall objective of the proposed project is to gain an understanding of how translational control mechanisms in the liver and the signaling pathways that regulate them respond to variations in macronutrients and the hormones insulin and glucagon, and in so doing provide insight into designing strategies for the treatment of disorders involving dysregulated metabolism. The general hypothesis to be tested is that nutrients and hormones activate both distinct and redundant cell signaling pathways in the liver, thus altering molecular mechanisms that mediate the regulation of mRNA translation, a process that contributes to the highly coordinated gene-expression patterns required to respond to fluctuations in the metabolic demands imparted on the tissue in a variety of physiological conditions. To test this hypothesis we propose the following specific aims: (1) identify the mechanisms that are responsible for mediating the action of glucagon to repress and the actions of free fatty acids and the branched-chain amino acid leucine to activate signaling through the mammalian target of rapamycin (mTOR) pathway to produce a change in the translational control of gene expression; (2) identify the mechanisms and signaling pathways that are responsible for producing a change in the translational control of gene expression in response to amino acid imbalance or unphysiologically low or high glucose concentrations; and (3) identify the molecular mechanism(s), the signaling pathways(s), and the nutritional and hormonal inputs through which translation of the albumin mRNA is derepressed in response to food intake. We expect to identify novel targets for therapeutic intervention under conditions in which the liver contributes to dysregulated metabolism.