Monocyte and macrophage Behavior in Atherosclerosis

描述（由申请人提供）：动脉粥样硬化是一种脂质驱动的炎性疾病，其特征为脂蛋白和白细胞在血管壁中的积聚。在白细胞中，巨噬细胞数量最多，对动脉粥样硬化的发展和恶化起决定性作用。病变巨噬细胞来源于循环单核细胞。在小鼠中，骨髓和脾来源的Ly-6Chigh单核细胞在病变中连续积累，并且在疾病过程中优先积累。我们最近的工作表明，除了单核细胞流入，成熟的巨噬细胞原位增殖。尽管病变巨噬细胞最终来源于循环单核细胞，但巨噬细胞增殖是已形成的动脉粥样硬化中巨噬细胞积聚的主要机制。协调单核细胞流入和巨噬细胞增殖的分子机制不同。一方面，单核细胞的产生和流入取决于生长因子和趋化因子。另一方面，局部巨噬细胞增殖部分依赖于通过清道夫受体SR-A的信号传导。在本研究中，我们假设单核细胞流入和巨噬细胞增殖的相对贡献是动脉粥样硬化发展和恶化的基础。我们建议配置文件的招聘和增殖的相对重要性，阐明和目标的分子机制，驱动这些过程，并关联巨噬细胞增殖与人类病变的组成。该研究具有临床相关性，因为靶向动脉粥样硬化中的特定炎症过程是主要的临床目标。因此，必须了解是否以及何时需要靶向单核细胞募集、巨噬细胞增殖或两者。

DESCRIPTION (provided by applicant): Atherosclerosis is a lipid-driven inflammatory disease characterized by the accumulation of lipoproteins and leukocytes in the vessel wall. Among the leukocytes, macrophages are the most numerous and contribute to the development and exacerbation of atherosclerosis decisively. Lesional macrophages derive from circulating monocytes. In the mouse, bone marrow and spleen-derived Ly-6Chigh monocytes accumulate in lesions continuously, and preferentially over the course of disease. Our recent work has shown that, in addition to monocyte influx, mature macrophages proliferate in situ. Although lesional macrophages ultimately derive from circulating monocytes, macrophage proliferation is a dominant mechanism of macrophage accumulation in established atherosclerosis. The molecular mechanisms that orchestrate monocyte influx and macrophage proliferation differ. On the one hand, production and influx of monocytes depends on growth factors and chemokines. On the other hand, local macrophage proliferation depends in part on signaling via the scavenger receptor SR-A. In the grant, we hypothesize that the relative contribution of monocyte influx and macrophage proliferation is fundamental to the development and exacerbation of atherosclerosis. We propose to profile the relative importance of recruitment and proliferation, elucidate and target the molecular mechanisms that drive these processes, and correlate macrophage proliferation with the composition of human lesions. The study is clinically relevant because targeting specific inflammatory processes in atherosclerosis is a major clinical goal. It is therefore essential to know whether and when monocyte recruitment, macrophage proliferation, or both, need to be targeted.