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，研究因果关系的潜在分子 胰岛素抵抗状态（如糖尿病和肥胖症）期间肝功能障碍的机制。收购 具体的培训，我将需要实现这一点，我提出了一个项目，使用国家的最先进的分子和 研究激素和营养物质如胰岛素和葡萄糖如何协调的生物化学方法 餐后状态下的肝脏代谢以及这些过程在代谢过程中如何被破坏 疾病我的职业发展计划将扩展我在激素信号方面的主要专业知识， 代谢生理学，并提供全基因组转录和生物信息学分析的基本培训， 和蛋白质生物化学由于我的目标是确定新的转录和信号机制， 调节肝脏代谢，我作为一个独立研究者的成功取决于这些技能。 目前的研究方向是研究肝葡萄糖激酶如何调节肝脏基因转录， 代谢以及这些过程如何导致糖尿病期间的代谢功能障碍。我开发了一个 分离肝脏对胰岛素和葡萄糖的反应的新型小鼠模型，这对于定义 每个信号在调节肝脏代谢中的具体贡献。葡萄糖激酶在肝细胞中的表达 缺乏肝脏Akt同种型的小鼠足以使葡萄糖耐量正常化并“经典地”调节 胰岛素反应基因。这些数据表明，葡萄糖信号的增加绕过了这一要求 在肝脏中直接作用胰岛素以调节转录和代谢。在这段指导生涯中 获得发展奖后，我将获得全基因组转录和蛋白质调控方面的专业知识 这些技术在我导师的实验室里已经很成熟了。我会验证一个假设 葡萄糖激酶对葡萄糖的利用导致异常的转录调节，从而导致葡萄糖耐受不良 和胰岛素抵抗。使用在K 01应用程序中学到的最先进的技术，我将定义 肝脏全基因组转录机制，有助于改变肝脏代谢在饮食- 诱导肥胖症和测试的转录因子Foxo 1在介导这些过程的要求。 此外，我将正式描述肝葡萄糖利用率降低和肝葡萄糖利用率升高之间的关系。 Foxo 1活性在胰岛素抵抗发生中的作用。最后，我将利用我新获得的专业知识， 转录分析，以确定调控机制和转录因子，除了Foxo 1， 负责协调肝脏对营养摄入的转录反应。这种指导支持 再加上我现有的专业知识，将提供一个成功的独立学术生涯的框架。