MECHANISMS OF DISEASE PREVENTION OF N-3 FATTY ACIDS

这项研究的目的是了解 细胞膜磷脂组成的变化 膜可以影响细胞和组织对损伤的反应。 磷脂的组成将通过富集法进行修饰 含长链、多不饱和n-3或n-6脂肪酸(PUFAs)。 已有研究表明，n-3多不饱和脂肪酸对冠状动脉有保护作用 人的疾病和抗实验性心脏缺血和 动物的大脑。它们也能保护人类免受遗传病的侵袭 模拟红斑狼疮的小鼠自身免疫性肾炎 在人类身上。这些多不饱和脂肪酸对缺氧的保护作用 肾小球系膜细胞损伤与炎性增殖 将在体外细胞系统中进行检测。保护作用，即 可能归因于从n-3产生的二十烷类化合物的改变 前体二十碳五烯酸以及可能的直接 浓缩磷脂含量对膜的影响 主要是二十碳五烯酸和二十二碳六烯酸，将是 检查过了。直接的膜效应将包括： 膜结合酶活性与抗药性 富含n-3脂肪酸的膜磷脂酶A-2； 线粒体呼吸作用的改变与钙离子敏感性 心、肾细胞的氧自由基损伤 饲喂高n-3脂肪酸含量的饲料的动物。中国政府的回应 富含n-3脂肪酸的培养肾小球系膜细胞 有丝分裂因子、血小板衍生生长因子与血小板 参与细胞炎症的激活因子 回应将会被确定。关于以下方面的具体假设 将对保护机制进行测试。 我们在这些模型系统中的发现应该与 增加对缺血性和炎症性损伤的认识 并帮助设计预防性的干预措施或 治疗这些普遍存在的疾病，这些疾病是主要原因 死亡和残疾在我们的社会中。

The object of this study is to learn the mechanisms by which alterations of membrane phospholipid composition of cell membranes can affect the response of cells and tissues to injury. The composition of phospholipids will be modified by enrichment with long chain, polyunsaturated n-3 or n-6 fatty acids (PUFAs). It has been shown that n-3 PUFAs protect against coronary artery disease in man and against experimental ischemia of heart and brain in animals. They also are protective against a hereditary antoimmune nephritis in mice which mimics lupus erythematosis in man. The effect of these PUFAs in protection against anoxic injury and the inflammatory proliferation of renal mesangial cells will be examined in in vitro cell systems. Protective effects, that may be attributed to altered eicosanoid production from the n-3 precursor, eicosapentaenoic acid, as well as to possible direct membrane effects produced by enriched phospholipid content primarily of eicosapentaenoic and docosahexaenoic acids, will be examined. The direct membrane effects will include: changes in membrane bound enzyme activities and resistance to phospholipase A-2 of membranes enriched with n-3 fatty acids; alterations in mitochondrial respiration and susceptibility to Ca2+ and oxygen free radical injury from heart and kidney cells of animals fed diets high in n-3 fatty acid content. The response of cultured mesangial cells enriched in n-3 fatty acids to potent mitogenic factors, platelet derived growth factor and platelet activating factor that participate in the cellular inflammatory response will be determined. Specific hypotheses regarding mechanisms of protection will be tested. Our findings in these model systems should be relevant to increasing understanding of ischemic and inflammatory injuries and in helping to design interventions that are preventive or therapeutic for these ubiquitous diseases which are major causes of death and disability in our society.