RAGE and Mechanisms of Vascular Dysfunction

RAGE 与血管功能障碍的机制

基本信息

批准号：
8768605
负责人：
Ravichandran Ramasamy
金额：
$ 119.09万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8768605
关键词：
Acute Adult Animal Model Apolipoprotein E Atherosclerosis Binding Biology Brain Hypoxia-Ischemia Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Cells Cellular Stress Cholesterol Chronic Cytoplasmic Tail Data Dependence Development Diabetes Mellitus Disease Endothelial Cells Functional disorder Gene Expression Regulation Genes Heart High Density Lipoproteins Human Hypoxia Imaging Techniques Immune response Incidence Inflammatory Injury Instruction Ischemia Knockout Mice Lead Ligands Link Measurement Mediating Mitochondria Molecular Monoclonal Antibodies Mus Myocardial Infarction Pathway interactions Peripheral arterial disease Play Positioning Attribute Property Protein Family Reagent Regulation Reperfusion Therapy Research Personnel Rodent Role Severities Shapes Signal Transduction Smooth Muscle Myocytes Stress Techniques Technology Testing Tissues United States Up-Regulation Vascular Diseases Ventricular Work Yeasts angiogenesis base cell motility cell type diabetic in vivo imaging innovation macrophage member mitochondrial permeability transition pore monocyte non-diabetic novel programs receptor receptor for advanced glycation endproducts tool yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The homozygous RAGE null mouse formed the centerpiece of discoveries during the last cycle of this Program. We demonstrated that RAGE plays critical roles in atheroscierosis in apoE null mice, mediates upregulation of pro-inflammatory and tissue-destructive genes in hypoxia, and mediates loss of cardiac function in the heart upon ischemia/reperfusion (l/R). Multiple novel findings shape the direction of our Program: first, we discovered that the RAGE cytoplasmic domain interacts with diaphanous-1 (mDia-1), a member of the formin homology domain protein family and an effector of RhoGTPases. mDia-1 is essential for RAGE ligand-mediated cellular migration and activation of cdc42/rac-1. New discoveries link mDial to key properties of smooth muscle cells, macrophages and cardiomyocyte signaling. Second, Project 2 has discovered the unanticipated finding that RAGE plays opposing roles in acute vs. chronic hypoxia/ischemia on regulation of Egr-1 in endothelial cells and monocytes/macrophages. Third, Project 1 has discovered that RAGE downregulates ABCG1 and cholesterol efflux to HDL. Fourth, Project 3 has discovered that deletion of mDial is highly protective in the heart in l/R. As a Program, we have shared not merely tools and strategies by virtue of our Core units but, more importantly, we have sought to understand the "big picture" of RAGE signaling. As our data unfold, we recognize that RAGE signaling is not "one size fits all," as new discoveries have uncovered distinct pathways of regulation by the receptor depending on cell type, duration of stress, and specific form of cellular stress. The challenge is to put it together. Toward this end, we have generated novel RAGE- and mDial floxed to probe cell-specific signaling of this axis in atherosclerosis (Project 1), angiogenesis (Project 2) and myocardial infarction (Project 3). Taken together, these discoveries form the basis of a highly innovative and significant set of questions testing RAGE and mDial signaling in vascular dysfunction in diabetic- and non-diabetic cardiovascular pathology. Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program.

描述（由申请人提供）：在该程序的最后一个循环中，纯合愤怒无效的愤怒无效的小鼠形成了发现的核心。我们证明，愤怒在ApoE Null小鼠中在动脉粥样硬化中起关键作用，介导缺氧促炎和组织毁灭性基因的上调，并介导缺血/再灌注（L/R）的心脏功能中心脏功能的丧失（L/R）。多个新颖的发现塑造了我们程序的方向：首先，我们发现愤怒的细胞质结构域与diaphanous-1（MDIA-1）相互作用，formin同源域蛋白质家族的成员和Rhogtpase的效应因子。 MDIA-1对于愤怒配体介导的细胞迁移和CDC42/RAC-1的激活至关重要。新发现将MDIAL与平滑肌细胞，巨噬细胞和心肌细胞信号的关键特性联系起来。其次，项目2发现了一个意外的发现，即愤怒在急性低氧/缺血中对内皮细胞和单核细胞/巨噬细胞中EGR-1的调节中的作用相反。第三，项目1发现愤怒下调了ABCG1和胆固醇外排对HDL。第四，项目3发现MDIAL的缺失在L/R中具有高度保护性。作为一个程序，我们不仅通过我们的核心单位分享了工具和策略，而且更重要的是，我们试图理解愤怒信号的“大局”。随着数据的展开，我们认识到愤怒信号并不是“一个大小”，因为新发现根据细胞类型，压力持续时间和细胞应力的特定形式发现了受体的不同调节途径。挑战是将它们放在一起。为此，我们已经产生了新型的愤怒和mdial，在动脉粥样硬化中（项目1），血管生成（项目2）和心肌梗塞（项目3）中，该轴的细胞特异性信号传导（项目3）。综上所述，这些发现构成了糖尿病和非糖尿病性心血管病理学中血管功能障碍中高度创新且重要的问题的基础。使用新颖和最先进的技术，floxed小鼠和基因调节的分子方法，我们对该程序的下一个周期中的愤怒进行了很好的态度。