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.

人体衰老伴随着心血管和血管内皮细胞的不可避免的发展 功能障碍，随着时间的推移，特别是当同时发生和叠加的与衰老相关的疾病增加时， 导致对缺血/再灌注(I/R)应激的易感性增加。作为对批评的回应，我们已经 开发并专注于使老年人健康的老化心血管系统的两个关键组成部分 生物体的放大损伤，包括先天和I/R。这些研究与项目1和2紧密相连。 这一计划的。首先，老年血管系统的基本炎症程度增加，特别是在老年人。 内皮细胞(EC)。其次，先天性心肌细胞功能障碍是随着年龄的增长而发展起来的。线粒体变成 心肌细胞随着年龄的增长而出现缺陷，从而增加活性氧的生成 损害三磷酸腺苷的生成。这种基本的损伤现象促进了增强细胞死亡的条件 -尤其是在I/R中。因此，在从老年动物中提取的EC和心肌细胞中，鉴定 这些发现背后的精确信号转导和转录调控机制是至关重要的。 在确定新的靶点以抑制不利的心血管衰老和减少放大的脆弱性方面 至I/R压力。我们将探讨这样一种假设，即多元醇酶AR活性的增加在衰老驱动中起作用 促进AGE生成的机制，从而招募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 提出当老年生物暴露于心脏叠加的I/R应激时，AR和AR增加 年龄-RAGE信号放大炎症和应激介质的产生，从而夸大损伤 老化的心脏。以与项目1和2(完整心脏)高度协同的方式，分离的EC和心肌细胞 将被用来探索信号转导和转录因子机制 调节老年心脏的基础和I/R应激。项目3与项目1和2共享小鼠/大鼠模型。 项目3将在赠款的所有五年期间使用计划项目的所有三个核心。