STRUCTURAL ANALYSIS OF APOLIPOPROTEIN A IN MICE

尽管Lp（a）作为致动脉粥样硬化的危险因素很重要， 缺乏信息，尤其是来自体内研究的信息 关于apo（a）的结构特征对Lp（a）的影响， 与血管壁的相互作用及其致动脉粥样硬化性质。 几乎所有拟议和已证实的亚太办事处活动（a）都集中在其 与纤溶酶原的高度序列同源性， 这些共同的特征和相关的 与纤溶酶原相互作用/竞争在体内决定Lp（a） 特性. 因此，这项建议的重点是通过基因改造， 载脂蛋白（a）分子的不同区域， 纤溶酶原，强调具有赖氨酸/纤维蛋白结合特性的纤溶酶原，和 然后在体外和体内评估这些变化的后果。 一 短期和长期方法相结合， 将进行工程小鼠，以检查：（1）apo（a） 赖氨酸/纤维蛋白结合位点在Lp（a）中起作用，并决定 这些位点是否在Lp（a）结合到 血管（短期腺病毒研究）：和（2）是否 载脂蛋白的赖氨酸/纤维蛋白结合特性（a）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，但机械地 相关的一系列分析，载脂蛋白（a）对各种 将评估包括动脉粥样硬化形成在内的血管参数， 纤溶酶原和纤维蛋白原敲除小鼠，以探索相互作用 在这些相关分子之间。 通过分析Lp（a）的作用， 赖氨酸/纤维蛋白结合位点对Lp（a）与纤溶酶原相互作用的影响， 血管和动脉粥样硬化，我们直接检查主要的 已经提出来解释 Lp（a）在人类中的生物学特性。 结构性和机械性 Lp（a）的体内活性的见解来自这些 研究可能有助于确定个体在动脉粥样硬化形成的风险， 高水平Lp（a）的基础，并发现潜在的目标， 开发治疗方法来解决这种动脉粥样硬化风险因素。

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.