Glucokinase Regulation of Hepatic Metabolism

葡萄糖激酶对肝脏代谢的调节

• 批准号: 9353795
• 负责人: Paul Michael Titchenell
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353795
• 关键词: Biochemical; Bioinformatics; Biomedical Research; Bypass; Carbohydrates; Clinical; Clinical Treatment; Clinical Trials; Coupled; Data; Data Set; Development; Development Plans; Diabetes Mellitus; Diet; Enhancers; Exclusion; FOXO1A gene; Fasting; Foundations; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Glucokinase; Glucose; Glucose Intolerance; Goals; Hepatic; Hormones; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Intake; K-Series Research Career Programs; Knock-out; Knowledge; Laboratories; Lead; Lipids; Liver; Measures; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Mutation Analysis; Nuclear; Nutrient; Obesity; Pathway interactions; Patients; Phosphorylation; Physiology; Positioning Attribute; Post-Translational Protein Processing; Process; Protein Biochemistry; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Public Health; Regulation; Regulatory Element; Research Personnel; Research Proposals; Signal Transduction; Techniques; Testing; Training; Transcriptional Regulation; base; career; career development; chromatin immunoprecipitation; diabetic patient; experimental study; feeding; genome-wide; global run on sequencing; glucose metabolism; glucose production; glucose tolerance; improved; insulin sensitivity; insulin signaling; knock-down; lipid metabolism; liver metabolism; mouse model; novel; response; skills; small molecule; success; tenure track; transcription factor; uptake

Project Summary My career goal is to lead a biomedical research group that investigates the causal underlying molecular mechanisms of hepatic dysfunction during insulin-resistant states such as diabetes and obesity. To acquire the specific training I will need to achieve this, I propose a project that uses state-of-the-art molecular and biochemical approaches to investigate how hormones and nutrients such as insulin and glucose coordinate hepatic metabolism in the postprandial state and how these processes become disrupted during metabolic disease. My career development plan will expand upon my primary expertise in hormone signaling and metabolic physiology and provide essential training in genome-wide transcriptional and bioinformatic analysis, and protein biochemistry. Since it is my goal to identify novel transcriptional and signaling mechanisms that regulate hepatic metabolism, my success as an independent researcher depends on these skills. The current research proposal is to study how hepatic glucokinase regulates liver gene transcription and metabolism and how these processes contribute to metabolic dysfunction during diabetes. I have developed a novel mouse model that dissociates the hepatic response to insulin and glucose, which is critical to define the specific contribution of each signal in regulating liver metabolism. Liver-specific expression of glucokinase in mice lacking hepatic Akt isoforms was sufficient to normalize glucose tolerance and to regulate “classically” defined insulin responsive genes. These data suggest increased glucose signaling bypasses the requirement of direct insulin action in liver to regulate transcription and metabolism. During this mentored career development award, I will gain the required expertise in genome-wide transcriptional and protein regulation techniques that are well established in my mentors' laboratories. I will test the hypothesis that defective glucose utilization by glucokinase leads to aberrant transcriptional regulation resulting in glucose intolerance and insulin resistance. Using state-of-the-art techniques learned during this K01 application, I will define the hepatic genome-wide transcriptional mechanisms that contribute to altered hepatic metabolism during diet- induced obesity and test the requirement of the transcription factor Foxo1 in mediating these processes. Moreover, I will formally delineate the relationship between reduced hepatic glucose utilization and increased Foxo1 activity in the development of insulin resistance. Finally, I will use my newly acquired expertise in transcriptional analysis to define the regulatory mechanisms and transcription factors, in addition to Foxo1, responsible for coordinating the hepatic transcriptional response to nutrient intake. This mentoring support coupled with my existing expertise will provide the framework for a successful independent academic career.

项目摘要 我的职业目标是领导一个生物医学研究小组，该小组研究因果关系基本分子 胰岛素耐药性状态（例如糖尿病和肥胖症）期间的肝功能障碍的机制 我将需要实现这一目标的具体培训，我提出了一个最先进的分子和 生化方法研究激素和胰岛素和葡萄糖等营养如何 餐后状态下的肝代谢以及这些过程在代谢过程中如何破坏 我的职业发展计划将扩大我的激素信号和 代谢生理学，并在全基因组转录和生物信息学分析中提供必要的培训， 和蛋白质生物化学。 调节肝代谢，我作为独立研究人员的成功取决于下一个技能。 当前的研究二甲苯是研究肝葡萄糖酶调节肝脏基因转录和 代谢以及这些过程如何导致代谢功能障碍。 分离肝脏对胰岛素和葡萄糖的肝反应的新型鼠标模型，这对于定义您的主题至关重要 每个信号在调节肝脏代谢中的特定贡献。 Micking Hepatic Akt Isofforms足以使葡萄糖耐量正常化并“经典” 定义的胰岛素反应基因表明，增加的葡萄糖信号绕过了需求 肝脏中直接胰岛素作用的调节转录和代谢。 开发奖，我将获得全基因组转录和蛋白质调节中所需的专业知识 在我的导师实验室中已经确立的技术。 葡萄糖酶利用葡萄糖酶的利用导致葡萄糖不耐症的额外转录调控结果 和胰岛素抵抗。 肝脏基因组全转录机制有助于饮食中肝的代谢改变 诱导肥胖并测试转录因子FOXO1在介导这些过程中的需求。 此外，我将正式描述减少的肝葡萄糖利用和增加之间的关系 FOXO1在胰岛素抵抗发展中的活性。 转录分析以定义调节机制和转录因子，除了FOXO1， 负责协调对营养摄入的肝转录反应。 再加上我现有的专业知识，将主要是成功的独立学术职业的框架。