Regulation of Liver Growth and Function

描述（由申请人提供）：营养素摄入超过能量消耗是肥胖和2型糖尿病在世界范围内流行的主要因素。传统上，营养素被认为是大分子生物合成的前体，也被认为是能量代谢分子产生的底物。然而，现在人们了解到它们通过信号传导级联反应来调节包括蛋白质合成在内的各种细胞过程。营养感应通路不仅在多个水平上相互连接，而且与胰岛素受体信号通路紧密耦合。因此，营养感应和胰岛素受体信号传导途径并不是孤立地发挥作用，而是作为一个更大的，整合的细胞内通讯系统的组成部分。本文提出的项目集中在肝脏，这是一个特别重要的器官，就身体的营养摄入的反应，因为它相对于胃肠道的位置，使其能够立即进入消化产品出现在门静脉。该项目还侧重于蛋白质合成，因为肝脏与胃肠道结合，占全身蛋白质合成反应的25%。最后，该项目侧重于翻译控制机制，PI实验室的专业知识得到了广泛认可，并且越来越多地被认为在基因表达调控中发挥着重要作用。该项目将采用非糖尿病和糖尿病小鼠，维持四种不同的饮食，旨在增加脂肪和热量的摄入。待检验的假设是，慢性营养过剩和糖尿病，单独或组合，通过翻译控制机制起作用，引起肝脏蛋白表达模式的整体和特异性变化，导致与代谢不良相关的病理学。通过以下三个具体目标来检验该假设：（1）确定不同饮食方案和糖尿病单独和组合对非糖尿病和糖尿病小鼠肝脏中蛋白质表达模式、由eIF 2和eIF 4F介导的翻译控制机制以及营养感应和胰岛素受体信号传导途径的激活状态的总体和特异性变化的影响;（2）定量非糖尿病和糖尿病小鼠肝脏中mTORC 1阻遏物REDD 1对营养过剩的反应，确定促进其上调表达的调控机制，并确定其作用机制;（3）阐明糖尿病诱导的高血糖和营养过剩介导翻译阻遏物4 E-BP 1肝脏表达增加的信号通路和分子机制。总的来说，该项目预计将产生新的知识，将提供深入了解设计策略，用于治疗与肥胖和糖尿病相关的适应不良的全身代谢引起的病理。

DESCRIPTION (provided by applicant): Nutrient intake in excess of energy expenditure is a major contributing factor to the world-wide epidemic of obesity and type 2 diabetes. Traditionally nutrients have been considered to be precursors for the biosynthesis of macromolecules and as substrates for the production of molecules involved in energy metabolism. However, they are now understood to act through signal transduction cascades to regulate various cellular processes including protein synthesis. The nutrient-sensing pathways are not only interconnected at multiple levels but are tightly coupled to the insulin receptor signaling pathway. Thus, nutrient-sensing and insulin receptor signaling pathways do not function in isolation, but rather as components of a larger, integrated system of intracellular communication. The project proposed herein focuses on the liver, which is an especially important organ in regards to the body's response to nutrient intake because of its position in relation to the gastrointestinal tract, affording it immediate access to the products of digestion appearing in the portal vein. The project also focuses on protein synthesis because the liver, in combination with the gastrointestinal tract, accounts for 25% of the whole body protein synthetic response to a mixed meal. Finally, the project focuses on translational control mechanisms, an area of research for which the expertise of the PI's laboratory is well recognized and one becoming increasingly recognized as playing a prominent role in the regulation of gene expression. The project will employ non-diabetic and diabetic mice maintained on four different diets designed to increase both the fat and caloric intake. The hypothesis to be tested is that chronic nutrient excess and diabetes, alone and in combination, acting through translational control mechanisms, cause both global and specific changes in hepatic protein expression patterns that contribute to pathologies associated with maladapted metabolism. The hypothesis will be tested by pursuing the three following specific aims: (1) define the effects of different dietary regimens and diabetes, alone and in combination, on global and specific changes in protein expression patterns, the translational control mechanisms mediated by eIF2 and eIF4F, and the activation state of nutrient- sensing and insulin receptor signaling pathways in the liver of nondiabetic and diabetic mice; (2) quantitate expression of the mTORC1 repressor REDD1 in the liver of nondiabetic and diabetic mice in response to nutrient excess, define regulatory mechanisms contributing to its upregulated expression, and define its mechanisms of action; and (3) elucidate the signaling pathways and molecular mechanisms through which diabetes-induced hyperglycemia and nutrient excess mediate increased hepatic expression of the translational repressor 4E-BP1. Overall, the project is expected to produce new knowledge that will provide insight into designing strategies for the treatment of pathologies resulting from the maladapted whole body metabolism associated with obesity and diabetes.