Function and Regulation of SR-A in Atherosclerosis

描述(由申请人提供)：尽管最近在降脂治疗方面取得了进展，但动脉粥样硬化仍然是心血管疾病的主要原因。SR-A主要由巨噬细胞表达，促进配体内化和细胞黏附。SR-A介导不同巨噬细胞功能的能力提示其在动脉粥样硬化的发病机制中可能具有多种作用。要了解SR-A在动脉粥样硬化中的作用，需要有能力独立研究SR-A介导的配体内化和巨噬细胞黏附。因此，识别调节SR-A功能的结构特征和细胞机制可能有助于理解该受体在动脉粥样硬化中的作用。我们的初步结果表明，SR-A介导的细胞黏附和配体内化涉及不同的细胞质结构域和不同的细胞内信号通路的激活。此外，我们的数据表明，SR-A的生理作用可能部分取决于SR-A的表达水平以及固定的和可溶的SR-A配体的相对丰度。因此，这一建议的假设是SR-A与修饰的基质蛋白结合，使SR-A与参与巨噬细胞黏附的细胞内信号蛋白定位，并促进巨噬细胞在动脉粥样硬化斑块中的聚集。介导细胞黏附而不是配体内化或介导配体内化但不是细胞黏附的受体结构的创建为我们提供了独特的试剂，使我们能够检验这一假说。我们的第一个目标是定义将SR-A连接到配体内化和细胞黏附的结构域。这些研究将确定SR-A通过内吞或吞噬介导的细胞黏附和配体内化所需的结构特征。我们的第二个目标是确定SR-A定位和功能之间的关系。在这一目标中提出的研究将使用生化和细胞生物学方法来检验以前未确定的SR-A在脂筏中的定位在区分SR-A介导的功能中的作用。我们的最终目标是确定SR-A介导的配体内化和巨噬细胞黏附在动脉粥样硬化形成中的重要性。这些研究利用骨髓移植方法来表达仅介导细胞黏附或配体内化的独特的SR-A结构，以确定这些功能在动脉粥样硬化中的相对贡献。总体而言，拟议研究的完成将进一步加深我们对SR-A在调节巨噬细胞功能和动脉粥样硬化形成中的作用的理解。有了这一认识，就有可能设计针对特定巨噬细胞功能的治疗方法，以减少动脉粥样硬化并增强降脂的益处。公共卫生相关性：尽管最近在降脂治疗方面取得了进展，但动脉粥样硬化仍然是心血管疾病的主要原因。A类清道夫受体(SR-A)是特别有趣的治疗靶点，因为它们介导多种活动，这些活动可能会不同地影响巨噬细胞参与动脉粥样硬化的发展。更好地了解SR-A在调节特定巨噬细胞功能中的作用，可能会发现新的治疗方法，将减少动脉粥样硬化，并将增强降脂的好处。

DESCRIPTION (provided by applicant): Despite recent advances in lipid lowering therapy, atherosclerosis remains a leading cause of cardiovascular disease. SR-A, which is primarily expressed by macrophages, promotes both ligand internalization and cell adhesion. The ability of SR-A to mediate different macrophage functions suggests that it may have multiple roles in the pathogenesis of atherosclerosis. Understanding the role of SR-A in atherosclerosis requires the ability to independently study SR-A-mediated ligand internalization and macrophage adhesion. Therefore, identifying the structural features and cellular mechanisms that regulate SR- A function may help in understanding the role of this receptor in atherosclerosis. Our preliminary results indicate that SR-A-mediated cell adhesion and ligand internalization involve distinct cytoplasmic domains and activation of different intracellular signaling pathways. Moreover, our data suggest that the physiologic role of SR-A may depend, in part, upon the level of SR-A expression and the relative abundance of immobilized and soluble SR-A ligand. Thus, the hypothesis of this proposal is that SR-A binding to modified matrix proteins localizes SR-A with intracellular signaling proteins involved in macrophage adhesion and promotes macrophage accumulation in atherosclerotic plaques. The creation of receptor constructs that mediate cell adhesion but not ligand internalization or mediate ligand internalization but not cell adhesion provides us with unique reagents that allow us to test this hypothesis. Our first aim is to define the structural domains that couple SR-A to ligand internalization and cell adhesion. These studies will define the structural features required for SR-A-mediated cell adhesion and ligand internalization via endocytosis or phagocytosis. Our second aim is to determine the relationship between SR-A localization and function. Studies proposed in this aim will use biochemical and cell biological approaches to examine a previously undefined role for SR-A localization in lipid rafts in distinguishing SR-A-mediated functions. Our final aim is to determine the importance of SR-A-mediated ligand internalization and macrophage adhesion in atherogenesis. These studies take advantage of a bone marrow transfer approach to express unique SR-A constructs that mediate only cell adhesion or ligand internalization to determine the relative contribution of these functions in atherosclerosis. Overall, completion of the proposed studies will further our understanding regarding the role of SR-A in regulating macrophage function and atherogenesis. With this understanding, it may be possible to design therapeutic approaches that target specific macrophage functions to reduce atherosclerosis and enhance the benefit of lipid lowering. PUBLIC HEALTH RELEVANCE: Despite recent advances in lipid lowering therapy, atherosclerosis remains a leading cause of cardiovascular disease. Class A scavenger receptors (SR-A) are particularly interesting therapeutic targets as they mediate multiple activities that may differentially affect macrophage participation in the development of atherosclerosis. A better understanding of the role of SR-A in regulating specific macrophage functions may identify new therapeutic approaches that will reduce atherosclerosis and will enhance the benefit of lipid lowering.