Role of TAZ in metabolic regulation in both normal and insulin resistant states

TAZ 在正常和胰岛素抵抗状态下代谢调节中的作用

• 批准号: 10314061
• 负责人: Ji Miao
• 金额: $ 45.15万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-10 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10314061
• 关键词: Binding; Biochemical Genetics; Blood Glucose; Cardiovascular Diseases; Cardiovascular system; Data; Diabetes Mellitus; Dyslipidemias; Fasting; Fatty Liver; Gene Expression; Genes; Glucose; Goals; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Hyperglycemia; Hypertriglyceridemia; Insulin Resistance; Knock-out; Knockout Mice; LXRalpha protein; Lipids; Liver; Metabolic; Metabolic Control; Metabolic Diseases; Molecular; Mus; Obesity; Organism; Pathogenesis; Pathologic; Pathway interactions; Physiological; Physiology; Plasma; Proteins; Regulation; Role; Series; Testing; Therapeutic Intervention; Tissues; Transcription Coactivator; Triglycerides; Up-Regulation; Work; blood glucose regulation; cell growth; chromatin immunoprecipitation; differential expression; feeding; genetic approach; genome-wide; glucocorticoid receptor alpha; glucose metabolism; glucose production; insight; lipid metabolism; liver metabolism; non-alcoholic fatty liver disease; novel therapeutics; overexpression; promoter; response; therapy development; transcriptome sequencing

Our long-term goal is to determine the molecular mechanisms that control metabolic homeostasis and there by identify therapies for metabolic diseases. While metabolic regulation is vital for an organism’s function and survival, metabolic dysregulation associated with insulin resistance gives rise to diabetes, non-alcoholic fatty liver disease, dyslipidemia, and cardiovascular disease. The goal of this project is to define the role of hepatic TAZ (transcriptional co-activator with PDZ binding motif) in the regulation of glucose and lipid metabolism in normal and insulin resistant states. Proteins that regulate cell growth overlap with those that control metabolic homeostasis. Therefore, we determined whether TAZ, which is known to control proliferation, regulates hepatic metabolism. Using molecular, biochemical, and genetic approaches, we obtained preliminary data which reveal that TAZ, independent of the Hippo pathway, is a unique regulator of energy homeostasis in the liver. Hepatic TAZ protein is dynamically altered by fasting and feeding, and TAZ regulates the differential expression of gluconeogenic and lipogenic genes in response to fasting and feeding. However, in insulin resistant states, the dysregulation of TAZ leads to perturbations of both glucose and lipid homeostasis. To build on this preliminary work, we propose a series of molecular and mouse studies to delineate the molecular mechanisms whereby hepatic TAZ regulates glucose and lipid metabolism in physiologic and pathologic insulin resistant states. Our aims are listed below. Specific Aim 1 is to define the role of hepatic TAZ in the regulation of gluconeogenic gene expression and glucose homeostasis. Specific Aim 2 is to define the role of hepatic TAZ in the regulation of de novo lipogenic gene expression and triglyceride homeostasis. We expect that our studies will define a new role for TAZ in metabolic regulation and will identify molecular mechanisms whereby glucose and lipid homeostasis are physiologically regulated. We also expect that our studies will provide mechanistic insights into the pathogenesis of insulin resistance, and thereby enable the development of therapies for insulin resistance-associated metabolic diseases, including diabetes, hepatosteatosis, dyslipidemia, and cardiovascular disease.

我们的长期目标是通过鉴定代谢疾病的疗法来确定控制代谢稳态的分子机制。尽管代谢调节对于生物体的功能和生存至关重要，但与胰岛素抵抗相关的代谢失调会导致糖尿病，非酒精性脂肪肝病，血脂异常和心血管疾病。该项目的目的是定义肝含量TAZ（转录）共激活因子与PDZ结合基序在正常和胰岛素抵抗状态下调节葡萄糖和脂质代谢的调节中的作用。调节细胞生长与控制代谢稳态的蛋白质。因此，我们确定了控制增殖的已知的TAZ是否调节肝素代谢。使用分子，生化和遗传方法，我们获得了初步数据，这些数据表明，与河马途径无关的TAZ是肝脏能量稳态的独特调节剂。肝TAZ蛋白通过禁食和喂养动态改变，TAZ调节糖原和脂肪生成基因的差异表达，以响应禁食和喂养。然而，胰岛素抵抗状态，TAZ的失调导致葡萄糖和脂质稳态的扰动。为了建立这项初步工作，我们提出了一系列分子和小鼠研究来描述分子机制，通过该机制，肝TAZ在生理和病理胰岛素耐药态中调节葡萄糖和脂质代谢。我们的目标在下面列出。具体目的1是定义肝TAZ在调节糖原性基因表达和葡萄糖稳态中的作用。具体目的2是定义肝TAZ在从头脂肪生成基因表达和甘油三酸酯稳态调节中的作用。我们预计我们的研究将定义TAZ在代谢调节中的新作用，并将确定葡萄糖和脂质稳态对分子机制进行物理调节。我们还期望我们的研究将提供有关胰岛素抵抗发病机理的机械见解，从而使胰岛素抵抗相关的代谢性疾病的疗法发展，包括糖尿病，肝炎，发作性血脂异常和心血管疾病。