Regulation of Liver Growth and Function

肝脏生长和功能的调节

• 批准号: 9304191
• 负责人: LEONARD S JEFFERSON
• 金额: $ 40.9万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304191
• 关键词: Acute; Affect; Attenuated; Biochemical; Cardiovascular Diseases; Chronic; Complex; Consumption; Counseling; Coupled; Data; Development; Diet; Dyslipidemias; EIF4EBP1 gene; Epidemic; Etiology; FRAP1 gene; Fatty Liver; Gene Expression; Gene Expression Profile; Genetic Transcription; Genetic Translation; Goals; Growth; Health; Hepatic; Hormones; Hyperglycemia; Hyperinsulinism; Hypertension; Inflammation; Insulin Resistance; Intervention; Knockout Mice; Knowledge; Laboratories; Lead; Lipids; Liver; Liver diseases; Long-Term Effects; Mediating; Messenger RNA; Metabolic; Metabolic syndrome; Metabolism; Mission; Modification; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Open Reading Frames; Pathogenesis; Pathway interactions; Pattern; Peptide Initiation Factors; Pharmacology; Phosphorylation; Polyribosomes; Population; Prevalence; Public Health; Regulation; Repression; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Site; Technology; Testing; Time; Translating; United States National Institutes of Health; Variant; Western World; detection of nutrient; endoplasmic reticulum stress; experience; insight; liver metabolism; mRNA Expression; non-alcoholic fatty liver; novel; prevent; protein expression; public health relevance; response; ribosome profiling; saturated fat; sedentary lifestyle; sugar; transcription factor; western diet

 DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of how diet and nutrients induce variation in signaling pathways and mechanisms to initiate alterations in translational control of hepatic gene expression that contribute to the pathogenesis of fatty liver disease. Continued existence of this gap represents an important problem because, until it is filled, understanding the etiology of fatty liver disease and developing interventions o prevent or reverse it will remain largely unfulfilled. Our long-term goal is to better understand te translational control of gene expression in the liver. The objective of the project proposed in thi application is to characterize translational control mechanisms and protein expression patterns that undergo acute variation in response to initiating consumption of a diet high in sugar and saturated fat (i.e. a Western diet). Our central hypothesis is that acute variation in protein expression in response to the diet is mediated through mechanisms involving the function of eIF4F and the 43S preinitiation complex. The rationale for the proposed research is that understanding diet-induced acute variation in these mechanisms has the potential to translate into better under-standing the pathogenesis of non-alcoholic fatty liver disease, a condition that affects about one-third of the US population. Guided by strong and in some cases novel preliminary findings, the hypothesis will be tested in the liver of mice following initiation of consumption of a Western diet by pursuing the following three specific aims: 1) Define variation in mTORC1 signaling and protein expression patterns; 2) Characterize expression and covalent modification (i.e. phosphorylation and O-GlcNAcylation) of initiation factors involved in assembly and function of eIF4F; and 3) Assess phosphorylation of the a-subunit of eIF2 as well as phosphorylation and GEF activity of eIF2B. Under the first aim, a novel mechanism suggested by our preliminary data for the Rheb- and Rag-mediated inputs to mTORC1 will be explored to develop an understanding of how the Western diet affects this hormone and nutrient sensing pathway. In addition, a recently developed technology that is now established in our laboratory will be used to identify variation in protein expression patterns. Under the second aim, we will extend our recent discovery of hyperglycemia-mediated O-GlcNAcylation of 4E-BP1 and eIF4G to studies on its role in regulating assembly and function of the eIF4F complex. Under the third aim, we will rely on our extensive experience in studies on assembly of the 43S preinitiation complex to gain an understanding of the relative roles of PERK and/or PKR-dependent phosphorylation of eIF2a and a corresponding reduction in eIF2B activity in protein expression from mRNAs with upstream open reading frames. The proposed research is significant because it is expected to advance and expand our understanding of how diet and nutrients can mediate variation in the patterns of gene expression in the liver leading to maladapted metabolism. Ultimately, such knowledge has the potential to inform development of both dietary counseling and pharmacologic intervention to prevent or reverse fatty liver disease.

 描述（由申请人提供）：我们对饮食和营养素如何诱导信号通路和机制的变化以启动肝脏基因表达翻译控制的改变（导致发病机制）的理解存在根本性差距 脂肪肝的症状这一差距的持续存在代表了一个重要的问题，因为在填补这一差距之前，了解脂肪肝疾病的病因并制定预防或逆转的干预措施在很大程度上仍将无法实现。我们的长期目标是更好地了解肝脏中基因表达的翻译控制。本申请中提出的项目的目的是表征翻译控制机制和蛋白质表达模式，其响应于开始食用高糖和饱和脂肪的饮食（即西方饮食）而经历急性变化。我们的中心假设是，蛋白质表达的急性变化，在饮食中介导的机制，涉及eIF 4F和43 S preinitiation复合物的功能。这项研究的基本原理是，了解这些机制中饮食引起的急性变化有可能转化为更好地理解非酒精性脂肪肝的发病机制，这种疾病影响了大约三分之一的美国人口。在强有力的和在某些情况下新颖的初步发现的指导下，通过追求以下三个具体目标，在开始食用西方饮食后的小鼠肝脏中测试该假设：1）确定mTORC 1信号传导和蛋白质表达模式的变化; 2）表征表达和共价修饰（即磷酸化和O-GlcNAc酰化）;和3）评估eIF 2的α-亚基的磷酸化以及eIF 2B的磷酸化和GEF活性。在第一个目标下，我们将探索Rheb和Rag介导的mTORC 1输入的初步数据所提出的一种新机制，以了解西方饮食如何影响这种激素和营养感应途径。此外，最近开发的技术，现在建立在我们的实验室将用于确定蛋白质表达模式的变化。在第二个目标下，我们将扩展我们最近发现的高血糖介导的4 E-BP 1和eIF 4G的O-GlcNAc酰化，以研究其在调节eIF 4F复合物的组装和功能中的作用。在第三个目标下，我们将依靠我们在43 S前起始复合物组装研究中的丰富经验，了解PERK和/或PKR依赖的eIF 2a磷酸化的相对作用，以及上游开放阅读框mRNA蛋白表达中eIF 2B活性的相应降低。这项拟议的研究意义重大，因为它有望推进和扩大我们对饮食和营养物质如何介导肝脏基因表达模式变异导致代谢失调的理解。最终，这些知识有可能为饮食咨询和药物干预的发展提供信息，以预防或逆转脂肪肝疾病。