Lipoprotein Receptors and Inflammation in the Vessel Wall

在动脉粥样硬化的发展过程中，单核细胞被募集到血管壁， 分化成巨噬细胞并加速这种疾病的发展。单核细胞分化是 与许多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，以及内吞和信号传导 受体，如低密度脂蛋白受体相关蛋白（LRP）。LDL受体家族 成员广泛表达，在脂蛋白代谢、蛋白酶降解 和信号传导通路。在本计划项目的前一个资助期内， 这项工作揭示了LRP调节多种生理事件。首先，使用寡聚核苷酸 通过微阵列数据，我们获得了LRP增加几种炎性细胞因子基因表达的证据。 细胞因子和趋化因子，包括MCP-1。第二，在与项目2的合作中，我们发现， 脑中活性tPA与LRP的结合导致血脑屏障的渗透性， 中风时局部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与整联蛋白Mac-1协同调节巨噬细胞迁移，从而调节巨噬细胞的增殖。 炎症本申请的中心假设是LRP调节炎性细胞中的炎症事件。 血管壁和具体的假设是：1）LRP调节炎症过程， 调节整联蛋白的功能性质，从而影响巨噬细胞迁移，2） 巨噬细胞LRP促进血管壁中脂蛋白的摄取，并有助于血管壁的发育。 3）LRP作为一种重要的吞噬受体发挥作用，并调节 通过涉及LRP的ICD释放的信号传导机制来抑制炎性细胞因子。这些假设将 1）研究LRP在血管损伤模型中的作用，并确定LRP在血管损伤模型中的作用。 LRP调节巨噬细胞迁移的机制2）研究巨噬细胞迁移的假设， LRP调节血管壁中的脂蛋白摄取，从而促进动脉粥样硬化; LRP在吞噬作用中的作用，并确定该事件是否触发了诱导LRP产生的信号级联。 炎症分子

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.