SCOR IN ARTERIOSCLEROSIS

一个关于脂蛋白及其如何诱导 提出了动脉粥样硬化。 目标是确定 脂蛋白与动脉壁的相互作用导致病变的形成。 在细胞水平，重点将放在相互作用 在脂蛋白和巨噬细胞和平滑肌细胞之间， 在某种程度上导致泡沫细胞产生的相互作用， 早期动脉粥样硬化病变的标志。 许多罚款的证据 低密度脂蛋白（LDL）的氧化修饰， 脂肪条纹形成的重要组成部分，但分子 所涉机制仍有待充分定性。 研究是 我提出了一个可以澄清这一点，同时提出新的方法， 其中氧化修饰可以在体外控制， 最终，在体内。 拟议计划的另一个主要组成部分 涉及单核细胞向组织巨噬细胞的分化， 试图定义基因表达的转录控制 在这种转变过程中，特别是与氧化有关的基因， 修饰LDL及其被巨噬细胞受体识别。 动物 研究旨在了解差异的原因， 动脉不同部位对动脉粥样硬化的易感性 墙 这些研究将利用生理和生物化学 包括原位杂交和PCR反应， 鉴定在易感部位和非易感部位表达的基因。 即使是非常微小的修饰LDL，包括氧化修饰 和糖基化，使其具有抗原性和自身抗体， 修饰形式已经在动物和人类中得到证实。 研究 提出进一步定义这些自身抗体，研究其 与冠状动脉疾病风险的相关性，并评估其 动脉粥样硬化的发病机制。 考虑到 建立证据表明LDL的氧化修饰在 在动脉粥样硬化形成中的作用，可能抑制这一过程的干预措施将是 在人类和实验动物身上进行了研究。 天然存在 抗氧化剂和合成抗氧化剂将被研究，以及 参与氧化修饰的酶的抑制剂。 的目标 这些临床研究的目的是提供信息， 临床干预试验最终可以以合理的方式进行规划。

A far-ranging program of research on lipoproteins and how they induce atherosclerosis is proposed. The goal is to establish the nature of the lipoprotein-artery wall interactions that contribute to lesion formation. At the cellular level, emphasis will be placed on the interactions between lipoproteins and macrophages and smooth muscle cells, interactions that somehow lead to the generation of foam cells, the hallmark of the earliest atherosclerotic lesion. Many fines of evidence point to oxidative modification of low density lipoprotein (LDL) as an important component of fatty streak formation but the molecular mechanisms involved remain to be fully characterized. Studies are proposed that could clarify this and, at the same time, suggest new ways in which oxidative modification might be controlled in vitro and, eventually, in vivo. Another major component of the proposed program relates to the differentiation of monocytes into tissue macrophage, attempting to define the transcriptional control of gene expression during that transition, especially of genes implicated in oxidative modification of LDL and its recognition by macrophage receptors. Animal studies are directed at understanding the reasons for differences in susceptibility to atherosclerosis of different regions in the artery wall. These studies will utilize physiological and biochemical approaches, including in situ hybridization and the PCR reaction to identify genes expressed in susceptible versus nonsusceptible sites. Even very minor modifications of LDL, including oxidative modification and glucosylation, make it antigenic and autoantibodies against these modified forms have been demonstrated in animals and in humans. Studies are proposed to further define these autoantibodies, to study their correlation with risk of coronary artery disease and to evaluate their contribution to the pathogenesis of atherosclerosis. In view of the building evidence that oxidative modification of LDL plays an important role in atherogenesis, interventions that may inhibit the process will be studied in humans and in experimental animals. Naturally occurring antioxidants and synthetic antioxidants will be studied as well as inhibitors of enzymes involved in oxidative modification. The goal of these clinical studies is to provide information on the basis of which a clinical intervention trial can eventually be planned in a rational way.