Aging & Vulnerability to Ischemia: Pathways & Rescue

老化

基本信息

批准号：
8775087
负责人：
ANN MARIE SCHMIDT
金额：
$ 122.18万
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：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2016-01-14
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：即使考虑了主要衰老相关疾病的考虑，人类受试者中心血管疾病倾向增强的主要因素也在促进年龄本身。该计划项目团队发现的发现突出了衰老生物学的新概念：首先，多元型途径酶还原酶（AR）的水平和活性在心脏中增加，尤其是在内皮细胞和心肌细胞中。 AR的上调产生了多种后果，包括产生二酰基甘油（DAG）和蛋白激酶C（PKC）的激活；并产生3个脱氧葡萄酮（3-DG）和甲基甘氨酸（MG），即晚期糖基化终产物（年龄）的前体。其次，在健康的年龄与年轻人和Fischer 344大鼠心脏中，尤其是在内皮细胞和心肌细胞中，在健康老年人和年轻人和菲舍尔心脏中增加了年龄和受体表达（RAGE）的受体表达。年龄与愤怒的相互作用与细胞和组织扰动和组织损伤密切相关。我们的计划建立在以下假设的基础上：AR质量衰老的组织在基础状态下进行扩增的心血管功能障碍。在叠加的I/R应力叠加后，至少部分通过增强的年龄产生和愤怒表达，增加了生化和分子信号会放大老年心脏的损伤。我们将在衰老和I/R应力中剖析这些途径的影响和相交，并确定关键信号通路，以调节基础老化和I/R胁迫心排气管系统中促炎和实现性基因的表达。该提议的计划将由三个独立但高度集成的项目组成，该项目由一个项目负责人团队领导，具有悠久的心血管生物学合作历史。项目1和2将分别探讨AR途径和愤怒在完整心脏中的作用。项目3将在孤立的EC和心肌细胞中探测AR和愤怒。这些研究将解决以下问题：衰老中的AR和愤怒的基础调节是否在衰老的心脏中，尤其是在内皮细胞和心肌细胞中，以便在I/R应激时放大损伤吗？这些途径是单独的，还是结合使用衰老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；以及转基因的老鼠和动物管理。这些努力将阐明将老化与增强I/R胁迫的脆弱性联系起来的机制，并有可能发现新的治疗干预措施，以抑制衰老心血管系统的I/R损伤。