Signaling Pathways Regulating the Activity of ChREBP by Glucose

葡萄糖调节 ChREBP 活性的信号通路

• 批准号: 7469548
• 负责人: ADAM J SHAYWITZ
• 金额: $ 3.63万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-26 至 2009-02-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469548
• 关键词: 14-3-3 Proteins; Acetylation; Affect; Binding Proteins; Biochemical; Biological Assay; Blood Glucose; Carbohydrates; Cell Line; Cell Nucleus; Cells; Condition; Cultured Cells; Cyclic AMP-Dependent Protein Kinases; Cytosol; Defect; Diabetes Mellitus; Disease; Disruption; Elevation; Emerging Technologies; Engineering; Exhibits; Family; Fatty acid glycerol esters; Gene Family; Genes; Genetic; Glucose; Glucose Transporter; Glycolysis; Goals; Hepatocyte; Incidence; Injection of therapeutic agent; Label; Laboratories; Lead; Libraries; Lipids; Lipodystrophy; Liver; Location; Mass Spectrum Analysis; Metabolic; Metabolic Control; Metformin; Methylation; Modification; Monitor; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Oxidative Stress; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Post-Translational Protein Processing; Prevention; Protein Kinase; Proteins; Public Health; Pyruvate Kinase; RNA Interference; Rare Diseases; Rate; Regulation; Reporter; Reporting; Resources; Response Elements; Role; STK11 gene; Serum; Signal Pathway; Signal Transduction; System; Tail; Techniques; Testing; Time; Up-Regulation; Veins; activating transcription factor; base; carbohydrate binding protein; carbohydrate receptor; extracellular; glucose metabolism; glucose uptake; hormone regulation; in vivo; insight; interest; intracellular protein transport; lipid metabolism; man; mature animal; member; mutant; novel; programs; protein expression; protein function; protein localization location; research study; response; transcription factor; upstream kinase

DESCRIPTION (provided by applicant): Project Summary The overarching goal of the proposed project is to better understand the intracellular and extracellular signals that regulate fat storage in the mature animal. From an evolutionary perspective, the ability of an organism to store energy in the form of fat when resources are plentiful is critical for its survival in ensuing times when resources are scarce. However, inappropriate fat storage can lead to multiple metabolic problems in man, including both common diseases such as obesity and type 2 diabetes as well as rarer disorders such as the lipodystrophies. The carbohydrate response-element binding protein (ChREBP) is a protein recently identified as playing a critical role in conversion of carbohydrate into fats. This factor responds to changes in serum glucose levels by activating cellular programs of lipid synthesis and storage, and mice lacking ChREBP exhibit significant alterations in lipid and glucose metabolism. AMP-dependent protein kinase (AMPK) is another well-characterized protein that senses intracellular energy and glucose but appears to function in a manner opposite to ChREBP. We and others have previously reported that the commonly used diabetes medication metformin relies on AMPK for exerting its beneficial effect on blood glucose. We wish to test the hypothesis that AMPK plays either a direct or indirect role as a negative regulator of ChREBP and that elevation in glucose uptake reduces AMPK activity and thus circumvents the negative regulation. The aims of this proposed project are to first identify the specific modifications on ChREBP induced by changes in serum glucose and then to investigate whether these modifications are consistent with the known activity of AMPK. These modifications will be identified using the technique of mass spectrometry, an emerging technology with which our laboratory has proven expertise. We also will test whether conditions that either enhance or inhibit AMPK activity lead to functional changes in ChREBP within the cell. We will then test whether genetic disruption of AMPK function, both in cultured cells as well as in mice, leads to changes in ChREBP activity. Relevance Type 2 diabetes and obesity are growing public health concerns both characterized by disordered fat metabolism. Identification of the specific molecules controlling fat synthesis and storage will provide new insights into these disorders and may potentially produce novel pharmacologic targets for treatment.

描述(由申请者提供)：项目摘要拟议项目的主要目标是更好地了解调节成熟动物脂肪储存的细胞内和细胞外信号。从进化论的角度来看，当资源充足时，有机体以脂肪的形式储存能量的能力对其在随后的资源稀缺时代的生存至关重要。然而，不适当的脂肪储存可能会导致人类的多种新陈代谢问题，包括肥胖症和2型糖尿病等常见疾病，以及脂肪营养不良等较为罕见的疾病。碳水化合物反应元件结合蛋白(ChREBP)是近年来发现的一种在碳水化合物转化为脂肪过程中起关键作用的蛋白质。该因子通过激活脂肪合成和储存的细胞程序对血清葡萄糖水平的变化做出反应，缺乏ChREBP的小鼠表现出显著的脂质和葡萄糖代谢变化。AMP依赖的蛋白激酶(AMPK)是另一种特性良好的蛋白质，它感知细胞内的能量和葡萄糖，但似乎以与ChREBP相反的方式发挥作用。我们和其他人之前已经报道过，常用的糖尿病药物二甲双胍依赖于AMPK发挥其对血糖的有利作用。我们希望验证这样一种假设，即AMPK作为ChREBP的负调节因子起直接或间接作用，并且葡萄糖摄取增加会降低AMPK活性，从而绕过负调节。这个项目的目的是首先确定血糖变化对ChREBP的特异性修饰，然后研究这些修饰是否与AMPK的已知活性一致。这些修改将使用质谱学技术进行识别，这是一项我们的实验室已被证明具有专业知识的新兴技术。我们还将测试增强或抑制AMPK活性的条件是否会导致细胞内ChREBP的功能变化。然后我们将测试AMPK功能的遗传破坏，无论是在培养细胞中还是在小鼠中，是否会导致ChREBP活性的变化。相关性：2型糖尿病和肥胖症都是以脂肪代谢紊乱为特征的日益严重的公共健康问题。识别控制脂肪合成和储存的特定分子将为这些疾病提供新的见解，并可能产生新的治疗药物靶点。