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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：
7341755
负责人：
MICHAEL S GOLIGORSKY
金额：
$ 28.76万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341755
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 Cycle Cell Size Cells Cessation of life Collagen Deceleration Development Diabetes Mellitus Disruption 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 Personal Satisfaction 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 Video Microscopy activation product antioxidant therapy base concept day design diabetic diabetic rat ebselen feeding human TNF protein in vivo intravital fluorescence microscopy mitochondrial dysfunction non-diabetic oxidized low density lipoprotein 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.

糖尿病患者心血管系统加速动脉粥样硬化和早衰