DETERMINANTS OF ATHEROSCLEROSIS PROTECTION

最近的发展为等离子体的作用提供了强有力的支持 脂蛋白在动脉粥样硬化斑块形成中的作用。 的目的 研究人类apo的最小结构特征 A-I（HuA-I）抑制和/或逆转动脉粥样硬化。 使用作为 两亲性螺旋基序是 在apo A-I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 类似物来定义这些最小的结构特征。 我们有 获得了令人兴奋的初步数据，表明肽模拟物 人载脂蛋白A-I（HuA-I）抑制饮食诱导的泡沫细胞形成 在小鼠中，和已知的自发损伤形成 在缺乏载脂蛋白E基因的小鼠中。 本提案将 在肽或突变体apoA-I转基因中进一步检验这一假设 在apoE基因敲除小鼠中，通过以下具体目的：1. 模型两亲性螺旋抗动脉粥样硬化作用的研究 缩氨酸 a. 腹腔注射或转基因表达， 形成富含脂质的泡沫细胞病变的饮食敏感小鼠。 B. 肽腹膜内施用或肽的表达 转基因小鼠缺乏载脂蛋白E基因将进行研究 肽抑制纤维损伤的能力。 2. 研究地点- 人载脂蛋白A-I的定向突变体。 a.设计与 载脂蛋白A-I突变体的研究。 B. 表达特征良好的 转基因小鼠模型中的apo A-I突变体。

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.