Function and Regulation of SR-A in Atherosclerosis

SR-A在动脉粥样硬化中的作用和调节

• 批准号: 7796782
• 负责人: Steven Post
• 金额: $ 36.25万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796782
• 关键词: Actins; Adhesions; Affect; Arterial Fatty Streak; Atherosclerosis; Bacteria; Binding; Biochemical; Biological; Bone Marrow; Cardiovascular Diseases; Cell Adhesion; Cells; Cholesterol; Complex; Cytoplasmic Tail; Data; Development; Disease; Disease Progression; Elements; Endocytosis; Focal Adhesions; Goals; Intracellular Signaling Proteins; Lesion; Ligands; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Membrane Microdomains; Mus; Mutation; Pathogenesis; Phagocytosis; Physiological; Proteins; Reagent; Regulation; Relative (related person); Research; Role; SR-A proteins; Signal Pathway; Signal Transduction; Testing; Therapeutic; Transgenic Organisms; Work; acetyl-LDL; atherogenesis; base; design; innovation; interest; macrophage; monocyte; novel therapeutic intervention; public health relevance; receptor; receptor expression; research study; therapeutic target; uptake

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.

描述（由申请人提供）：尽管脂质降低治疗的最新进展，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，促进了配体内在化和细胞粘附。 SR-A介导不同巨噬细胞功能的能力表明，它可能在动脉粥样硬化的发病机理中具有多个作用。了解SR-A在动脉粥样硬化中的作用需要独立研究SR-A介导的配体内在化和巨噬细胞粘附的能力。因此，确定调节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介导的细胞粘附和配体内在化涉及不同的细胞质结构域以及不同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表达水平以及固定和可溶的SR-A配体的相对丰度。因此，该建议的假设是SR-A与改性基质蛋白的结合将SR-A定位在SR-A中，细胞内信号传导蛋白参与巨噬细胞粘附，并促进动脉粥样硬化斑块中的巨噬细胞积累。创建介导细胞粘附而不是配体内在化或介导配体内在化而不是细胞粘附的受体构建体为我们提供了独特的试剂，使我们能够检验该假设。我们的第一个目的是定义将SR-A与配体内在化和细胞粘附相对的结构域。这些研究将定义SR-A介导的细胞粘附和配体内在化所需的结构特征。我们的第二个目的是确定SR-A定位与功能之间的关系。在此目标中提出的研究将使用生化和细胞生物学方法来检查脂质筏中SR-A定位的先前未定义的作用，以区分SR-A介导的功能。我们的最终目的是确定SR-A介导的配体内在化和巨噬细胞粘附在动脉粥样硬化中的重要性。这些研究利用骨髓转移方法来表达仅介导细胞粘附或配体内在化的独特SR-A构建体，以确定这些功能在动脉粥样硬化中的相对贡献。总体而言，提出的研究的完成将进一步了解SR-A在调节巨噬细胞功能和动脉粥样硬化中的作用。有了这种理解，可能可以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提高脂质降低的好处。公共卫生相关性：尽管脂质降低疗法最近进展，但动脉粥样硬化仍然是心血管疾病的主要原因。 A类寻宝受体（SR-A）是特别有趣的治疗靶点，因为它们介导了多种活动，这些活动可能会差异地影响巨噬细胞参与动脉粥样硬化的发展。更好地理解SR-A在调节特定巨噬细胞功能中的作用，可以鉴定出新的治疗方法，从而减少动脉粥样硬化，并将提高脂质降低的益处。