Lipoprotein Receptors and Inflammation in the Vessel Wall

在动脉粥样硬化的发展过程中，单核细胞被招募到血管壁，在那里他们 分化为巨噬细胞，加速本病的发展。单核细胞分化是 与一些巨噬细胞受体的上调有关，包括模式识别 清道夫和Toll样受体参与先天免疫以及内吞和信号转导 受体，如低密度脂蛋白受体相关蛋白(LRP)。这个低密度脂蛋白受体家族 成员广泛表达，在脂蛋白代谢、蛋白水解酶的降解、 以及在信号通路中。在本计划项目的前一个资助期内，授予我们的 研究表明，LRP调节一系列不同的生理事件。首先，使用寡核苷酸 基因芯片数据显示，我们获得的证据表明LRP增加了几种炎症性细胞的基因表达 细胞因子和趋化因子，包括单核细胞趋化蛋白-1。第二，与项目2合作，我们发现 活性tPA与脑内LRP的结合导致血脑屏障的通透性，从而导致 中风时因缺血引起的损伤增加。第三，在与项目3的合作中，我们发现 LRP与整合素Mac-1协同调节巨噬细胞的迁移，从而调节 发炎。这一应用的中心假设是LRP调节炎症事件在 血管壁和需要检验的具体假设是：1)LRP通过以下方式调节炎症过程 调节整合素的功能特性，从而影响巨噬细胞的迁移，2) 巨噬细胞LRP促进血管壁脂蛋白摄取并参与血管发育 3)LRP是一种重要的吞噬细胞受体并调节其产生 通过释放LRP的ICD的信号机制，促进炎症细胞因子的产生。这些假设将 测试的目的如下：1)研究LRP在血管损伤模型中的作用，并确定 LRP调节巨噬细胞迁移的机制2)研究了巨噬细胞 LRP调节血管壁脂蛋白摄取，从而促进动脉粥样硬化和3)评估 LRP在吞噬作用中的作用，并确定这一事件是否触发了诱导产生 炎性分子。

During the development of atherosclerosis, monocytes are recruited to the vessel wall where they differentiate into macrophages and accelerate the development of this disease. Monocyte differentiation is associated with the up-regulation of a number of macrophage receptors, including pattern-recognition scavenger and toll-like receptors that are involved in innate immunity, as well as endocytotic and signaling receptors such as the low density lipoprotein receptor-related protein (LRP). This LDL receptor family member is widely expressed and plays important roles in lipoprotein metabolism, degradation of proteases, and in signaling pathways. During the previous funding period of this program project grant the results of our work revealed that LRP modulates a diverse range of physiological events. First, using oligionucleotide microarray data, we obtained evidence that LRP increases the gene expression of several inflammatory cytokines and chemokines, including MCP-1. Second, in collaboration with project 2, we discovered that association of active tPA with LRP in the brain leads to permeability of the blood brain barrier resulting in increased damage induced by ischemia during stroke. Third, in collaboration with project 3 we found that LRP cooperates with the integrin Mac-1 to modulate macrophage migration thereby modulating inflammation. The central hypothesis of this application is that LRP regulates inflammatory events in the vessel wall and the specific hypotheses to be tested are: 1) that LRP regulates inflammatory processes by modulating the functional properties of integrins and thereby affects macrophage migration, 2) that macrophage LRP promotes the uptake of lipoproteins in the vessel wall and contributes to the development of atherosclerosis, 3) that LRP functions as an important phagocytic receptor and modulates the production of inflammatory cytokines via a signaling mechanism involving release of LRP's ICD. These hypotheses will be tested in the following aims: 1) Investigate the role of LRP in a vascular injury model and identify mechanisms by which LRP modulates macrophage migration 2) Investigate the hypothesis that macrophage LRP modulates lipoprotein uptake in the vessel wall thereby promoting atherosclerosis and 3) Evaluate the role of LRP in phagocytosis and determine if this event triggers signaling cascades that induce production of inflammatory molecules.