Aging & Vulnerability to Ischemia: Pathways & Rescue

描述（由申请方提供）：即使在考虑了主要的衰老相关疾病后，人类受试者心血管疾病倾向增强的主要因素是年龄本身的增长。该项目团队发现的发现突出了衰老生物学中的新概念：首先，心脏中多元醇途径酶醛糖还原酶（AR）的水平和活性增加，特别是在内皮细胞和心肌细胞中。AR的上调导致多种后果，包括二酰基甘油（DAG）的产生和蛋白激酶C（PKC）的活化;以及3-脱氧葡糖醛酮（3-DG）和甲基乙二醛（MG）的产生，它们是晚期糖基化终产物（AGEs）的前体。第二，AGEs的积累和晚期糖基化终产物受体（Receptor for Advanced Glycation Endproducts，RECEPTOR）的表达在健康老年人与年轻人和Fischer 344大鼠心脏中增加，特别是在内皮细胞和心肌细胞中。AGE与血管紧张素Ⅱ的相互作用与细胞和组织扰动以及组织损伤密切相关。我们的计划是建立在这样的假设上的，即AR在基础状态下引发老年组织的心血管功能障碍。在叠加I/R应激时，至少部分地通过增强的AGE产生和AGEs表达，增加的生化和分子信号放大了老年心脏的损伤。我们将剖析这些途径在衰老和I/R应激中的影响和交叉，并确定调节基础衰老和I/R应激心血管系统中促炎和促血栓形成基因表达的关键信号通路。 该计划将由三个独立但高度集成的项目组成，由一个在心血管生物学方面具有长期合作历史的项目负责人团队领导。项目1和2将分别探讨AR通路和AR在完整心脏中的作用。项目3将在分离的EC和心肌细胞中探测AR和AR。这些研究将解决的问题：是否基础调制AR和AR在老化的启动老年心脏，特别是在内皮细胞和心肌细胞，放大损伤后I/R的压力？这些途径单独或组合是否是衰老过程中心血管保护的新目标？拟议的计划项目将得到三个核心的支持：行政和生物统计学;动物实验和分析;和转基因小鼠和动物管理。这些努力将揭示衰老与I/R应激脆弱性增强的机制，并可能发现新的治疗干预措施来抑制衰老心血管系统的I/R损伤。

DESCRIPTION (provided by applicant): Even after accounting for the major aging-associated diseases, the major factor underlying the enhanced propensity to cardiovascular diseases in human subjects is advancing age itself. Findings uncovered by this Program Project team highlight new concepts in the biology of aging: First, the level and activity of the polyol pathway enzyme aldose reductase (AR) is increased in heart, particularly in endothelial cells and cardiomyocytes. Multiple consequences ensue from upregulation of AR, including generation of diacylglycerol (DAG) and activation of Protein Kinase C (PKC); and production of 3 deoxyglucosone (3-DG) and methylglyoxal (MG), precursors of Advanced Glycation Endproducts (AGEs). Second, accumulation of AGEs and expression of Receptor for Advanced Glycation Endproducts (RAGE) is increased in healthy aged vs. young human and Fischer 344 rat hearts, especially in endothelial cells and cardiomyocytes. The interaction of AGE with RAGE is linked intimately to cellular and tissue perturbation and tissue injury. Our Program is built on the hypothesis that AR primes aged tissues for amplified cardiovascular dysfunction in the basal state. Upon superimposed I/R stress, at least in part via enhanced AGE generation and RAGE expression, increased biochemical and molecular signals amplify injury in the aged heart. We will dissect the influence and intersection of these pathways in aging and I/R stress, and determine the key signaling pathways that modulate expression of pro-inflammatory and prothrombotic genes in basal aging and I/R- stressed cardiovasculature. This proposed Program will consist of three independent but highly integrated projects, led by a team of project leaders with a long history of collaboration in cardiovascular biology. Projects 1 & 2 will probe the role of AR pathway and RAGE in the intact heart, respectively. Project 3 will probe AR and RAGE in isolated EC and cardiomyocytes. These studies will address the questions: does basal modulation of AR and RAGE in aging prime the aged heart and, particularly, in endothelial cells and cardiomyocytes, for magnified injury upon I/R stress? Are these pathways, alone, or in combination, novel targets for cardiovascular protection in aging? The proposed Program Project will be supported by three cores: Administrative and Biostatistics; Animal Experimentation and Analysis; and Transgenic Mouse and Animal Management. These endeavors will shed light on mechanisms linking aging to enhanced vulnerability to I/R stress, and, potentially, uncover new therapeutic interventions to suppress I/R injury in the aging cardiovascular system.