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.

我们的长期目标是确定控制代谢稳态的分子机制，从而确定代谢疾病的治疗方法。虽然代谢调节对于有机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、非酒精性糖尿病。该项目的目标是确定肝脏 TAZ（具有 PDZ 结合基序的转录共激活剂）在正常和胰岛素抵抗的葡萄糖和脂质代谢调节中的作用。调节细胞生长的蛋白质与控制代谢稳态的蛋白质重叠，因此，我们利用分子、生化和遗传方法确定了已知控制增殖的 TAZ 是否调节肝脏代谢。独立于 Hippo 途径，是肝脏能量稳态的独特调节剂。肝脏 TAZ 蛋白通过禁食和进食动态改变，并且 TAZ 调节糖异生和脂肪生成基因的差异表达。然而，在胰岛素抵抗状态下，TAZ 的失调会导致葡萄糖和脂质稳态的扰动。在这项初步工作的基础上，我们提出了一系列分子和小鼠研究来描述肝脏 TAZ 调节的分子机制。生理和病理胰岛素抵抗状态下的葡萄糖和脂质代谢 我们的目标如下：明确肝脏 TAZ 在糖异生基因表达和葡萄糖的调节中的作用。具体目标 2 是确定肝脏 TAZ 在从头脂肪生成基因表达和甘油三酯稳态调节中的作用，我们期望我们的研究将确定 TAZ 在代谢调节中的新作用，并确定葡萄糖和脂质的分子机制。我们还期望我们的研究将为胰岛素抵抗的发病机制提供机制见解，从而能够开发出与胰岛素抵抗相关的代谢疾病的疗法，包括糖尿病、肝脂肪变性、血脂异常和心血管疾病。