INTERACTIONS OF LP(A) WITH SUBENDOTHELIAL CELL MATRIX

最近的研究支持了这样一种观点，即Lp(A)水平的增加 与冠状动脉疾病风险增加相关， 载脂蛋白(A)在动脉壁内积聚。这样做的主要目标是 建议是定义参与相互作用的成分 Lp(A)与内皮下细胞外基质结合并探讨其可能性 这种互动的后果。这一目标基于这样的假设： Lp(A)‘S与内皮下细胞外基质的相互作用 加速动脉粥样硬化的进程 富含胆固醇酯的脂蛋白(ApoB-LP)和 止血因素。为了检查本论文的某些方面， 提出了以下具体目标：具体目标1.确定是否 Lp(A)与内皮下细胞外基质结合促进 其他含有载脂蛋白B的脂蛋白的积累。具体目标2. 确定Lp(A)与内皮下层的结合是否 细胞外基质促进各种止血物质的蓄积 因子(凝血因子VII、蛋白C、凝血酶原、组织纤溶酶原 激活剂等)。具体目标3.确定哪些成分是 内皮下细胞外基质负责结合 Lp(A)的亲和力。具体目标4.定义分子基础 脂蛋白(A)与载脂蛋白B的相互作用 内皮下细胞外基质。具体目标5.制定方法论 并监测结合的止血因素的后果 脂蛋白-细胞外基质界面。电泳法分析， 生化分离，分离脂蛋白种类的特征 和细胞外成分，细胞生物学，配基和免疫印迹， 分子生物学的单抗、工具和方法，数字 用于定量和结合分析以及定量分析的成像 脂类和载脂蛋白是一些将被 用来实现这些特定的目标。这项建议应该提供新的 脂蛋白(A)/载脂蛋白(A)与载脂蛋白B关系的研究 脂蛋白对血管内皮细胞外基质的影响 动脉硬化。它还应该更好地定义 止血因子与载脂蛋白B和脂蛋白的相互作用 载脂蛋白(A)和载脂蛋白B结合内皮下的特定结构域 细胞外基质、止血因子，以及它们之间的关系。这些研究 应该能更好地理解血浆 脂蛋白、止血系统和血管紧张素转换酶的进展 动脉硬化。

Recent studies have supported the view that increased levels of Lp(a) are associated with increased risk of coronary artery disease and the accumulation of Apo(a) in the arterial wall. The principal goal of this proposal is to define the constituents involved in the interactions of Lp(a) with the subendothelial extracellular matrix and explore possible consequences of this interaction. This goal is based on the hypothesis: Lp(a)'s interactions with the subendothelial extracellular matrix accelerate the atherosclerotic process by contributing to the accumulation of cholesterol ester rich lipoproteins (ApoB-Lp) and hemostatic factors. To examine some aspects of this thesis, the following specific aims are presented: Specific aim 1. Determine whether the binding of Lp(a) to the subendothelial extracellular matrix promotes the accumulation of other ApoB-containing lipoproteins. Specific aim 2. Determine whether the binding of Lp(a) to the subendothelial extracellular matrix promotes the accumulation of various hemostatic factors (Factor VII, Protein C, prothrombin, tissue plasminogen activator, etc.). Specific aim 3. Determine which constituents of the subendothelial extracellular matrix are responsible for the binding affinity of Lp(a). Specific aim 4. Define the molecular basis for the interactions of Lp(a) with ApoB-containing lipoproteins and the subendothelial extracellular matrix. Specific aim 5. Develop methodology and monitor the consequences of bound hemostatic factors at the lipoprotein-extracellular matrix interface. Electrophoretic analyses, biochemical separations, characterization of isolated lipoprotein species and extracellular components, cell biology, ligand and immunoblotting, monoclonal antibodies, tools and approaches of molecular biology, digital imaging for quantitative and binding analyses, and quantitative analyses of lipids and apolipoproteins are some of the methodologies which will be used to achieve these specific aims. This proposal should provide new insights into the relationship of Lp(a)/ Apo(a) and ApoB-containing lipoproteins to the subendothelial extracellular matrix in atherosclerosis. It should also give a better definition of the role of interactions of hemostatic factors with ApoB-containing lipoproteins and the particular domains of Apo(a) and ApoB that bind subendothelial extracellular matrix, hemostatic factors, and each other. These studies should provide a better understanding of the link between plasma lipoproteins, the hemostasis system, and the progression of atherosclerosis.