PREVENTION OF VASCULOPATHY AND NEPHROPATHY IN METABOLIC SYNDROME

预防代谢综合征中的血管病变和肾病

基本信息

批准号：
7990210
负责人：
MICHAEL S GOLIGORSKY
金额：
$ 10.1万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-15 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990210
关键词：
3-nitrotyrosine Advanced Glycosylation End Products Aging-Related Process Animals Antioxidants Apoptosis Apoptotic Atherosclerosis Biochemical CDKN2A gene Cardiovascular system Cell Aging Cell Count Cell Culture Techniques Cell Cycle Cell Size Cells Cessation of life Collagen Deceleration Development Diabetes Mellitus Endothelial Cells Enrollment Epidemic Event Extracellular Matrix Proteins Extravasation Fatty acid glycerol esters Fructose Functional disorder Galactosidase Gangliosides General Population Human Image Analysis In Vitro Incidence Insulin Resistance Investigation Kidney Kidney Diseases Lead Life Light Mediating Metabolic Metabolic syndrome Microcirculation Mitochondria Modeling Molecular Molecular Target Morphology Mus North America Obesity Oxidative Stress Oxygen Consumption Pathway interactions Patients Permeability Peroxonitrite Phase II Clinical Trials Phenotype Population Premature aging syndrome Prevention Production Protein Kinase C Proteins Rattus Role Superoxides Syndrome TP53 gene Techniques Treatment Efficacy Tumor Necrosis Factor-alpha Umbilical vein Vascular Diseases Video Microscopy antioxidant therapy base design diabetic diabetic rat ebselen feeding human TNF protein in vivo intravital fluorescence microscopy mitochondrial dysfunction non-diabetic oxidized low density lipoprotein premature prevent receptor for advanced glycation endproducts research study senescence

项目摘要

Accelerated atherosclerosis and premature aging of the cardiovascular system in patients with diabetes mellitus and metabolic syndrome have acquired epidemic proportions. Our previous studies of endothelial cells subjected to a microenvironment emulating the diabetic milieu revealed accelerated development of cell senescence. Based on the observations that the expression of nitrotyrosine-modified proteins was enhanced in the prematurely senescent cells and peroxynitrite treatment of intact cells led to premature senescence, we treated endothelial cells with a bona fide peroxynitrite scavenger/antioxidant ebselen. Such a treatment was associated with the prevention and reversal of premature senescence. These findings prompted us to investigate the molecular mechanism(s) of premature cell senescence, effects of ebselen on premature endothelial cell senescence in a model of metabolic syndrome - Zucker diabetic rats, and examine the development of vasculopathy in these animals. We hypothesize that oxidative stress/peroxynitrite-induced lysosomal dysfunction initiates endothelial cell senescence and accumulation of gangliosides, a molecular switch from senescence to apoptosis- events underpinning the progression of vasculopathy. In vitro and in vivo studies employing image analysis and fluorescence intravital microscopy, biochemical techniques to detect leakage of lysosomal and mitochondria! proteins as well as accumulation of gangliosides, and quntitative analysis of the markers of cell cycle are designed to investigate molecular and cellular mechanisms of premature senescence and apoptosis. In vivo studies of the Zucker diabetic fat rat treated with ebselen will be conducted to examine the possibility of preventing and reversing macro- and micro-vasculopathy (nephropathy) in this syndrome. The investigations may shed light on mechanisms of premature senescence of endothelial cells, role of peroxynitrite in initiating it, and potential therapeutic efficacy of peroxynitrite scavenging in amelioration of vasculopathy.

加速糖尿病患者心血管系统的动脉粥样硬化和过早衰老 Mellitus和代谢综合征已获得流行比例。我们以前关于内皮的研究经过微环境模仿糖尿病环境的细胞显示出加速的发展细胞衰老。基于观察到硝基酪氨酸改性蛋白的表达是在过早的衰老细胞和完整细胞的过氧亚硝酸盐治疗中增强了导致过早的衰老，我们用真正的过氧硝酸盐清除剂/抗氧化剂Ebselen处理了内皮细胞。这种治疗与预防和逆转过早衰老有关。这些调查结果促使我们研究了过早细胞衰老的分子机制 Ebselen在代谢综合征模型的早产内皮细胞衰老中 - 扎克糖尿病大鼠，检查这些动物中血管病的发育。我们假设该氧化应力/过氧亚硝酸盐诱导的溶酶体功能障碍启动内皮细胞衰老和积累神经节苷脂，从衰老到细胞凋亡的分子转换 - 支撑的进展血管病。体外和体内研究采用图像分析和荧光插入显微镜，生化技术可检测溶酶体和线粒体的泄漏！蛋白质和积累神经苷剂和细胞周期标志物的量化分析旨在研究分子和过早衰老和凋亡的细胞机制。扎克糖尿病脂肪的体内研究将进行Ebselen处理的大鼠，以检查预防和逆转宏观和该综合征中的微观排气病（肾病）。调查可能会阐明内皮细胞的过早衰老，过氧亚硝酸盐在启动它中的作用以及潜在的治疗性过氧亚硝酸盐在改善血管病的功效。