STRUCTURAL ANALYSIS OF APOLIPOPROTEIN A IN MICE

尽管Lp(A)作为动脉粥样硬化的危险因素很重要，但 缺乏信息，特别是来自活体研究的信息。 关于载脂蛋白(A)的哪些结构特征对LP(A)有贡献，S 与血管壁的相互作用及其致动脉粥样硬化的特性。 APO(A)几乎所有拟议和已证实的活动都侧重于其 与纤溶酶原高度同源性和强 这些共享功能和关联的可能性 与纤溶酶原相互作用/竞争决定体内Lp(A)S 属性。因此，这项提议的重点是从基因上修改 载脂蛋白(A)分子的不同区域与 纤溶酶原强调具有赖氨酸/纤维蛋白结合特性的那些，以及 然后在体外和体内评估这些变化的后果。一个 短期和长期相结合的遗传方法 将进行工程小鼠，以检查：(1)什么载脂蛋白(A) Lp(A)中的赖氨酸/纤维蛋白结合位点是功能性的，并确定 这些位点是否在与Lp(A)结合中发挥核心作用 血管系统(短期腺病毒研究)：和(2)是否 载脂蛋白(A)的赖氨酸/纤维蛋白结合特性对动脉粥样硬化形成的影响 小鼠(长期转基因研究)。在一个单独的但机械的 相关系列分析，载脂蛋白(A)对生物多样性的影响 包括动脉粥样硬化形成在内的血管参数将在 纤溶酶原和纤维蛋白原基因敲除小鼠的相互作用 在这些相关分子之间。通过分析LP(A)的作用 Lp(A)与纤溶酶原相互作用上的赖氨酸/纤维蛋白结合部位 血管系统和动脉粥样硬化形成，我们正在直接检查主要的 已经提出的解释这种现象的机制路径 Lp(A)在人体内的生物学特性。结构性和机械性 对Lp(A)体内活性的洞察将由此而来 研究可能有助于确定老年人动脉粥样硬化形成的风险。 根据高水平的Lp(A)并发现潜在的目标 针对这种动脉粥样硬化危险因素的治疗方法的发展。

Despite the importance of Lp(a) as an atherogenic risk factor, a paucity of information, especially from in vivo studies, is available concerning what structural features of apo(a) contribute to Lp(a)'s interactions with the vessel wall and its proatherogenic properties. Nearly all of the proposed and proven activities of apo(a) focus on its high degree of sequence homology with plasminogen and the strong possibility that these shared features and associated interaction/competition with plasminogen determine Lp(a)'s in vivo properties. The focus of this proposal is thus to genetically modify various regions of the apo(a) molecule that are shared with plasminogen emphasizing those with lysine/fibrin biding properties, and then assess in vitro and in vivo the consequences of these changes. A combination of short- and long-term approaches to genetically engineer mice will be performed in order to examine: (1) what apo(a) lysine/fibrin binding sites are functional in Lp(a) and determine whether these sites lay a central role in Lp(a) binding to the vasculature (short-term adenoviral studies): and (2) whether the lysine/fibrin binding properties of apo(a) impact on atherogenesis in mice (long-term transgenic studies). In a separate but mechanistically related series of analyses, the impact of apo(a) on the variety of vascular parameters including atherogenesis will be assessed in plasminogen and fibrinogen knockout mice to explore the interactions between these related molecules. Through analyzing the role of Lp(a) lysine/fibrin binding sites on interactions of Lp(a) with plasminogen, the vasculature and atherogenesis, we are directly examining the major mechanistic pathways which have been proposed to explain the biological properties of Lp(a) in humans. Structural and mechanistic insights into the in vivo activities of Lp(a) to be derived from these studies may help define individuals at risk for atherogenesis on the basis of high-levels of Lp(a) and uncover potential targets for the development of therapies to address this atherosclerosis risk factor.