DETERMINANTS OF ATHEROSCLEROSIS PROTECTION

最近的发展为血浆的作用提供了强有力的支持 动脉粥样硬化斑块形成中的脂蛋白。这样做的目的是 建议研究人类载脂蛋白的最小结构特征 A-I(HUA-I)抑制和/或逆转动脉粥样硬化。用作 工作假说，两亲性螺旋基序是 在载脂蛋白A-I中的主要结构和功能域，我们有 开始使用模型两亲性螺旋肽进行动物实验 类比来定义那些最小的结构特征。我们有 获得了令人兴奋的初步数据，表明多肽模拟 人载脂蛋白A-I(HUA-I)抑制饮食诱导的泡沫细胞形成 在小鼠身上，以及已知的自发病变形成 在缺乏载脂蛋白E基因的小鼠身上放置。本提案将 在多肽或突变型载脂蛋白A-I转基因中进一步验证这一假设 并在载脂蛋白E基因敲除小鼠中通过以下特定目的：1. 模型两亲性螺旋对动脉粥样硬化保护作用的研究 多肽。A.腹膜内注射或转基因表达 对饮食敏感的小鼠，形成富含脂肪的泡沫细胞病变。B. 多肽腹腔注射或多肽的表达 将对缺乏载脂蛋白E基因的小鼠进行转基因研究 多肽抑制纤维性病变的能力。2.对遗址的研究- 人载脂蛋白A-I的定向突变体A.设计和 载脂蛋白A-I突变体的研究B.表达有良好特征的 转基因小鼠模型中的载脂蛋白A-I突变。

Recent developments provide strong support for the role of plasma lipoproteins in atherosclerotic plaque formation. The aim of this proposal is to study the minimal structural features of human apo A-I (HuA-I) that inhibit and/or reverse atherosclerosis. Using as a working hypothesis that the amphipathic helical motif is the predominant structural and functional domain in apo A-I, we have begun animal experiments using model amphipathic helical peptide analogs to define those minimal structural features. We have obtained exciting preliminary data indicating that peptide mimics of human apo A-I (HuA-I) inhibit diet-induced foam cell formation in mice, and spontaneous lesion formation that is known to take place in mice lacking the apo E gene. The present proposal will test this hypothesis further in peptide or mutant apo A-I transgenic and in apo E knockout mice via the following specific aims: 1. Studies of atherosclerosis protection by model amphipathic helical peptides. a. Intraperitoneal injection or transgenic expression in diet-sensitive mice that form lipid-rich foam cell lesions. b. Peptide intraperitoneal administration or expression of peptide transgenes in mice lacking the apo E gene will be done to study the ability of peptide to inhibit fibrous lesions. 2. Studies of site- directed mutants of human apolipoprotein A-I. a. Design and study of apo A-I mutants. b. Expression of well-characterized apo A-I mutants in transgenic mouse models.