Homocysteine: Vascular Biochemistry and Metabolism

同型半胱氨酸：血管生物化学和代谢

基本信息

批准号：
7822182
负责人：
Donald Weldon Jacobsen
金额：
$ 1.82万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2009-06-01 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822182
关键词：
Accounting Adverse effects Affect Albumins American Antioxidants Atherosclerosis Biochemistry Blood Circulation Blood Vessels Cardiovascular Diseases Cardiovascular system Cell physiology Cells Clinical Research Cysteine Diet Disulfides End stage renal failure Endoplasmic Reticulum Endothelial Cells Equilibrium Etiology Folic Acid Functional disorder Genetic Genotype Growth Factor Health Benefit Homeostasis Homo Homocysteine Homocystine Human Hyperhomocysteinemia Impaired cognition Incidence Inflammatory Intervention Laboratories Lead Link Macroglobulins Mediating Mediator of activation protein Metabolism Metallothionein Molecular Target Monocyte Chemoattractant Protein-1 Morbidity - disease rate Myocardial Infarction NF-kappa B Neural Tube Defects Nutrient Osteoporosis Pathology Patients Plasma Play Pregnancy Complications Primary Prevention Process Proteins Proteome Proteomics Public Health Refractory Research Research Personnel Risk Factors Role Signal Transduction Smooth Muscle Myocytes Source Stroke Sulfhydryl Compounds System Text Therapeutic Intervention Up-Regulation Vascular Endothelium Work Zinc atherogenesis conventional therapy cytokine enantiomer extracellular high risk improved insight loss of function mortality novel programs protein function research study response

项目摘要

DESCRIPTION (provided by applicant): Hyperhomocysteinemia is a modifiable, independent risk factor for cardiovascular disease, cognitive dysfunction, complications of pregnancy, and osteoporosis. Homocysteine-induced endothelial cell dysfunction may link this diverse group of pathologies. Our research has focused on: 1) the vascular biochemistry of homocysteine; 2) the mechanism of homocysteine transport in cultured human aortic endothelial cells; and, 3) the molecular targeting of protein cysteine residues by homocysteine. Thiol-disulfide exchange accounts for the forms of homocysteine in circulation. Cysteine transporters mediate homocysteine import in the vascular endothelium. Evidence is provided that links homocysteine targeting to vascular cell dysfunction. The long-term objectives are to understand the mechanism of homocysteine-accelerated atherogenesis and to develop improved interventional strategies that will lower plasma total homocysteine in high-risk subjects and in subjects who are refractory to conventional therapy (e.g., end-stage renal disease). Our central hypotheses are: 1) homocysteine is a mediator of early atherogenesis but becomes a marker in advanced atherosclerosis (we call this the "mediator ?>? marker hypothesis" of hyperhomocysteinemia); 2) monocyte chemoattractant protein 1 and other pro-inflammatory cytokines are induced by homocysteine in early atherogenesis by a mechanism involving the activation of NF-kB; 3) the fundamental mechanism underlying homocysteine causality is molecular targeting; and, 4) homocysteine-lowering by primary intervention will reduce mortality and morbidity associated with hyperhomocysteinemia. Our specific aims are: 1) to study the mechanism of protein homocysteinylation and functional consequences; 2) to study the transport and metabolism of homocysteine and its disulfide congeners in vascular cells; and, 3) to identify intracellular proteins (e.g., metallothionein) targeted by homocysteine and how loss of function of targeted proteins leads to vascular cell dysfunction. The program to fortify the American diet with folic acid, completed in January, 1998, has had a profound effect on reducing the incidence of hyperhomocysteinemia, neural tube defects and, possibly, mortality due to stroke and heart attack. Additional public health benefits are likely by gaining a better understanding of homocysteine transport, metabolism and the adverse effects of homocysteine on our circulatory system.

描述（由申请人提供）：高同型半胱氨酸血症是心血管疾病、认知功能障碍、妊娠并发症和骨质疏松症的可改变的独立危险因素。同型半胱氨酸诱导的内皮细胞功能障碍可能将这组不同的病理联系起来。我们的研究重点是：1）同型半胱氨酸的血管生化； 2）培养人主动脉内皮细胞同型半胱氨酸转运机制； 3) 同型半胱氨酸对蛋白质半胱氨酸残基的分子靶向。硫醇-二硫化物交换解释了循环中同型半胱氨酸的形式。半胱氨酸转运蛋白介导血管内皮中同型半胱氨酸的输入。有证据表明同型半胱氨酸靶向与血管细胞功能障碍有关。长期目标是了解同型半胱氨酸加速动脉粥样硬化形成的机制，并开发改进的干预策略，以降低高危受试者和常规治疗难治性受试者（例如终末期肾病）的血浆总同型半胱氨酸。我们的中心假设是：1）同型半胱氨酸是早期动脉粥样硬化形成的介质，但成为晚期动脉粥样硬化的标志物（我们称之为高同型半胱氨酸血症的“介质？>？标志物假说”）； 2) 单核细胞趋化蛋白1和其他促炎细胞因子在早期动脉粥样硬化形成中由同型半胱氨酸诱导，其机制涉及NF-kB的激活； 3）同型半胱氨酸因果关系的根本机制是分子靶向； 4) 通过初级干预降低同型半胱氨酸将降低与高同型半胱氨酸血症相关的死亡率和发病率。我们的具体目标是：1）研究蛋白质同型半胱氨酸化的机制和功能后果； 2）研究同型半胱氨酸及其二硫键同系物在血管细胞中的转运和代谢； 3) 识别同型半胱氨酸靶向的细胞内蛋白（例如金属硫蛋白）以及靶向蛋白功能丧失如何导致血管细胞功能障碍。用叶酸强化美国人饮食的计划于 1998 年 1 月完成，对降低高同型半胱氨酸血症、神经管缺陷以及可能因中风和心脏病引起的死亡率产生了深远的影响。通过更好地了解同型半胱氨酸的转运、代谢以及同型半胱氨酸对我们循环系统的不利影响，可能会带来额外的公共健康益处。