AMPK, Metabolic and Inflammatory Stress and the Endothelial Cell

AMPK、代谢和炎症应激以及内皮细胞

基本信息

批准号：
8230872
负责人：
NEIL B RUDERMAN
金额：
$ 29.99万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230872
关键词：
5&apos -AMP-activated protein kinase AMP-activated protein kinase kinase Affect Animals Aorta Apoptosis Atherosclerosis Attenuated Blood Vessels Blood capillaries Caloric Restriction Capillarity Cell Adhesion Molecules Cells Central obesity Chemicals Confidential Information Cultured Cells Deacetylase Disease Down-Regulation Dyslipidemias Endothelial Cells Endothelium Enzymes Event Exercise Fatty Acids Functional disorder Funding Glucose Goals Grant Health Histones Human Hyperglycemia Hypertension Hypoglycemia Inflammation Inflammatory Insulin Resistance Ionophores Ischemia Language Liver Mediating Metabolic Metabolic syndrome Metformin Mission Mitochondria Modification Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Palmitates Phenformin Phenotype Predisposition Protein phosphatase Proteins Public Health Rattus Regulation Research Research Design Research Methodology Resveratrol Rodent Role STK11 gene Signal Transduction Stimulus Stress Techniques Testing Thrombin Training Tumor Necrosis Factor-alpha Vascular Endothelial Cell Vascular Endothelial Growth Factors angiogenesis atherogenesis capillary density deprivation human TNF protein in vivo inhibitor/antagonist insight lipid metabolism mitochondrial dysfunction novel premature prevent response

项目摘要

State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of ; the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe v the rationale and techniques you will use to pursue these goals. i In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this i description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE : PROVIDED. The metabolic syndrome has been defined clinically as a disorder characterized by dyslipidemia, hypertension, central obesity and a predisposition to premature atherosclerotic cardiovascular disease and type 2 diabetes. It is also associated with capillary rarefaction and impaired angiogenesis in muscle. In the preceding grant periods, we demonstrated that AMPK is operative in cultured vascular endothelial cells '(HUVEC, HAEC) and that its activation protects them against the apoptosis, inflammation and mitochondrial (dysfunction caused by incubation in media enriched in glucose, palmitate or TNF-alpha. In addition, we demonstrated the existence of a Sirt1/LKB1/AMPK signaling mechanism in various cultured cells and in rat liver in vivo and we have obtained preliminary evidence for its presence in cultured endothelium. In project 1, we will extend this research by carrying out studies with the following objectives: 1) To characterize the roles of Sirtl and LKB1 in mediating AMPK activation by such factors as glucose deprivation, phenformin, and resveratrol in cultured endothelial cells; 2) To determine whether hyperglycemia induces insulin resistance and apoptosis and enhances TNF-alpha - induced adhesion molecule expression in endothelial cells by causing AMPK dysregulation (decreased activity or impaired activation). If as anticipated it does, we would then determine whether this dysregulation involves inhibition pf the Sirt1/LKB1 mechanism [possibly by post-translational oxidative modification of SirT1 (with project 2)], and/or activation of protein phosphatases; and 3) To examine whether AMPK-mediated events in the vasculature are impaired in vivo in mice with endothelial-cell specific deletions of either SirT1 or LKB1. Studies will be done in cre/lox mice that will be generated by Dr. Walsh (Core B), which he will use to study ischemia-induced angiogenesis (Project 3), and Dr. Cohen (Project 2) atherogenesis in the aorta. We will characterize the effects of exercise in these and in control mice together with Dr. Nathan LeBrasseur, a rodent exercise physiologist. In particular, we will determine how SirT1 and LKB1 downregulation affect the increase in muscle capillary density and the decrease in atherogenic changes in the aorta that typically occur in response to exercise in rodents with a metabolic syndrome phenotype. j - ¿ ^These studies will provide the first information about the function of the SirT1/LKB1/AMPK signaling mechanism in the vasculature. They should also provide novel insights as to whether its dysregulation could be a cause of the endothelial cell dysfunction associated with the metabolic syndrome and a target for its therapy. ,

陈述该应用程序的广泛，长期目标和具体目标，提及 ;该项目（即与代理机构的任务相关）。简单地描述实现这些目标的研究设计和方法。描述 v您将用来追求这些目标的基本原理和技术。另外，我用两到三个句子，简单地描述这项研究与公共卫生的相关性。如果申请是资助的，则我描述将成为公共信息。因此，请勿包含专有/机密信息。不要超过空间：假如。代谢综合征在临床上被定义为以血脂异常为特征的疾病，高血压，中枢肥胖和过度动脉粥样硬化心血管疾病和 2型糖尿病。它也与毛细血管稀疏性和肌肉中的血管生成受损有关。在在授予期之前，我们证明了AMPK在培养的血管内皮细胞中运行 '（HUVEC，HAEC）并且其激活可以保护它们免受细胞凋亡，炎症和线粒体的侵蚀（富含葡萄糖，棕榈酸酯或TNF-Alpha的培养基引起的功能障碍。此外，我们证明了在各种培养细胞和大鼠中存在SIRT1/LKB1/AMPK信号传导机制生活在体内，我们已经获得了其在培养的森林中存在的初步证据。在项目1中我们将通过以下目标进行研究来扩展这项研究：1）表征 SIRTL和LKB1在介导AMPK激活中通过葡萄糖剥夺等因素的作用在培养的内皮细胞中的苯甲酸和白藜芦醇； 2）确定是否高血糖诱导胰岛素抵抗和凋亡，并增强TNF -α诱导的粘附分子通过引起AMPK失调（活性降低或受损）在内皮细胞中的表达激活）。如果按预期的是，我们将确定这种失调是否涉及抑制 PF SIRT1/LKB1机制[可能是通过SIRT1的翻译后氧化修饰（带有项目2）]，和/或蛋白质磷酸酶的激活； 3）检查AMPK介导的事件是否在脉管系统在体内受损的小鼠，具有SIRT1或SIRT1或 LKB1。研究将在将由Walsh博士（Core B）生成的Cre/Lox小鼠中进行，他将使用该研究研究缺血引起的血管生成（项目3）和主动脉中的Cohen博士（项目2）动脉粥样硬化。我们将与Nathan Lebrasseur博士一起表征这些运动和对照小鼠中运动的影响啮齿动物运动生理学家。特别是，我们将确定SIRT1和LKB1下调如何影响肌肉毛细血管密度的增加以及主动脉症中的动脉粥样硬化变化的降低通常发生响应代谢综合征表型的啮齿动物运动。 J-� ^这些研究将提供有关SIRT1/LKB1/AMPK信号传导功能的第一个信息脉管系统中的机制。他们还应该就其失调是否可以提供新颖的见解成为与代谢综合征相关的内皮细胞功能障碍的原因，其目标是治疗。，，，，