AR & AGE-RAGE IN AGING: IMPACT ON ENDOTHELIAL AND VASCULAR STRESS

增强现实

• 批准号: 8042640
• 负责人: SHI FANG YAN
• 金额: $ 21.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8042640
• 关键词: 1,2-diacylglycerol; 3-deoxyglucosone; Address; Adenoviruses; Advanced Glycosylation End Products; Age; Aging; Animals; Antigens; Atherosclerosis; Automobile Driving; Biochemical; Blood Vessels; C57BL/6 Mouse; CCAAT-Enhancer-Binding Proteins; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cell Death; Cells; Cellular Stress; Cessation of life; Collaborations; Complement; Coronary artery; Coupled; Critiques; Data; Development; Diabetes Mellitus; Diglycerides; Disease; Dominant-Negative Mutation; Dose; Employee Strikes; Endothelial Cells; Endothelium; Enzymes; Functional disorder; Generations; Genetic; Genetic Models; Grant; Heart; Histocompatibility Testing; Human; Hydrogen Peroxide; Hypertension; Hypoxia; Inbred F344 Rats; Inflammation; Inflammation Mediators; Inflammatory; Injury; Ischemia; L-Iditol 2-Dehydrogenase; Link; Mediating; Mediator of activation protein; Messenger RNA; Mitochondria; Modeling; Mus; Muscle Cells; NF-kappa B; Organism; Oxidative Stress; Oxidoreductase; PPET; Pathway interactions; Phenotype; Principal Investigator; Process; Production; Protein Kinase C; Proteins; Publishing; Pyruvaldehyde; Rattus; Reactive Oxygen Species; Reagent; Recruitment Activity; Reperfusion Injury; Reperfusion Therapy; Resources; Role; Signal Transduction; Small Interfering RNA; Stress; Tail; Techniques; Testing; Time; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Organisms; Up-Regulation; Vascular Endothelial Cell; Ventricular; Wild Type Mouse; Work; age related; aged; base; biological adaptation to stress; caspase-9; cell age; cell injury; cell type; emergency service responder; human subject; in vitro Model; inhibitor/antagonist; insight; juvenile animal; middle age; mutant; novel; polyol; proendothelin 1; programs; promoter; receptor; receptor for advanced glycation endproducts; research study; response; transcription factor; vascular endothelial dysfunction; vascular inflammation

Aging in human subjects is accompanied by the inevitable development of cardiovascular and endothelial dysfunction, which, over time, especially as co-incident and superimposed aging-related disorders mount, leads to a heightened vulnerability to ischemia/reperfusion (I/R) stress. In response to the critique, we have developed and focused this project on two key components of aging cardiovasculature that prime the aged organism for amplified injury, both innately, and upon I/R. These studies are tightly coupled to Projects 1 & 2 of this Program. First, basal degrees of inflammation increase in aged vasculature, particularly in aged endothelial cells (EC). Second, innate cardiomyocyte dysfunction develops in aging. Mitochondria become defective in cardiomyocytes as they age and increase generation of reactive oxygen species (ROS), thereby impairing ATP generation. Such fundamental injury phenomena promote conditions for enhanced cell death - especially in I/R. Thus, in both EC and cardiomyocytes retrieved from aged animals, identification of the precise signal transduction and transcriptional regulation mechanisms underlying these findings is essential in identifying novel targets to suppress adverse cardiovascular aging and diminish the amplified vulnerability to I/R stress. We will probe the hypothesis that increased activity of the polyol enzyme AR in aging drives mechanisms that enhance generation of AGE, thereby recruiting RAGE and consequent signal transduction in EC and cardiomyocytes; mechanisms which we predict are linked to cardiovascular dysfunction. We propose that when aged organisms are exposed to superimposed I/R stress in the heart, increased AR and AGE-RAGE signaling amplify production of inflammatory and stress mediators that exaggerate injury in the aged heart. In a manner highly synergistic with Projects 1&2 (intact heart), isolated EC and cardiomyocytes from aged animals will be used to probe the signal transduction and transcription factor mechanisms that regulate basal and I/R stress in the aged heart. Project 3 shares mouse/rat models with Projects 1 and 2. Project 3 will utilize all three Cores of the Program Project during all five years of the grant.

人类的衰老不可避免地伴随着心血管和内皮细胞的发展 功能障碍，随着时间的推移，特别是随着同时发生和叠加的与衰老相关的疾病的增加， 导致更容易遭受缺血/再灌注（I/R）应激。为了回应批评，我们 该项目开发并重点关注衰老心血管系统的两个关键组成部分，为老年人做好准备 生物体会产生先天性和 I/R 后的放大损伤。这些研究与项目 1 和 2 紧密结合 本计划的。首先，老年脉管系统的基础炎症程度增加，尤其是老年人 内皮细胞（EC）。其次，先天性心肌细胞功能障碍随着衰老而发生。线粒体成为 随着年龄的增长，心肌细胞会出现缺陷并增加活性氧（ROS）的产生，从而 损害 ATP 生成。这种基本的损伤现象促进了细胞死亡的增加 - 特别是在 I/R 方面。因此，在从老年动物中获取的 EC 和心肌细胞中，鉴定出 这些发现背后的精确信号转导和转录调控机制至关重要 确定新的目标来抑制不利的心血管衰老并减少放大的脆弱性 I/R 压力。我们将探讨多元醇酶 AR 活性增加促进衰老的假设 增强 AGE 生成的机制，从而募集 RAGE 和随后的信号转导 在 EC 和心肌细胞中；我们预测的机制与心血管功能障碍有关。我们 提出当衰老的生物体暴露于心脏中叠加的 I/R 应激时，AR 和 AGE-RAGE 信号放大炎症和应激介质的产生，从而加剧损伤 年老的心。与项目 1 和 2（完整心脏）、分离的 EC 和心肌细胞高度协同 来自老年动物的信号将被用于探测信号转导和转录因子机制 调节老年心脏的基础压力和 I/R 压力。项目 3 与项目 1 和 2 共享小鼠/大鼠模型。 项目 3 将在拨款的五年内利用该计划项目的所有三个核心。