Monocyte Heterogeneity in Experimental and Human Atherosclerosis

描述(申请人提供)：动脉粥样硬化是一种复杂的慢性疾病，也是心肌梗死和中风的主要原因。目前，治疗动脉粥样硬化的主要概念性方法包括操纵脂代谢和操纵炎症过程。尽管付出了许多努力，但动脉粥样硬化并发症的死亡率仍在继续上升。单核细胞和巨噬细胞被广泛认为是动脉粥样硬化的关键细胞主角；它们不仅通过释放炎症介质促进疾病，而且作为富含脂肪的泡沫细胞，它们成为疾病物理体积的一部分。尽管它们的不分青红皂白的靶向会干扰正常的动态平衡和免疫，因此在治疗上是不可行的，但单核细胞在人类、小鼠和其他哺乳动物中由不同的亚群组成的发现表明了功能的专门化，并激发了人们对区分有害和有益亚群的方法的兴趣。在这项建议中，我们将检验这一假设，即单核细胞亚群在动脉粥样硬化形成中的作用不同，并且可以选择性地靶向成像和治疗疾病。实验将利用经典的细胞生物学工具、分子图谱和最近开发的体内分子成像和治疗技术，允许在多个分辨率下询问单核细胞生物学，从整个动物到单个细胞。该项目将与当地成像、免疫学和心血管小组以及外部合作者密切互动。靶向单核细胞亚群的能力将促进我们对动脉粥样硬化形成的理解，并可能使我们能够评估旨在选择性抑制单核细胞亚群募集或功能的药物，并对有发生动脉粥样硬化并发症(如心肌梗死或中风)的患者进行分层。公共卫生相关性：动脉粥样硬化是一种慢性疾病，也是心脏病发作和中风的主要原因。被称为单核细胞的免疫细胞在疾病的发展过程中起着重要作用。这笔拨款将调查是否有可能通过靶向这些细胞来治疗动脉粥样硬化。

DESCRIPTION (provided by applicant): Atherosclerosis is a complex chronic disease and a leading cause of myocardial infarction and stroke. At present, the dominant conceptual approaches to therapy for atherosclerosis involve manipulation of lipid metabolism and manipulation of inflammatory processes. Despite numerous efforts, mortality rates for complications of atherosclerosis continue to rise. Monocytes and macrophages are widely regarded as key cellular protagonists of atherosclerosis; not only do they promote disease through release of inflammatory mediators, but also, as lipid-rich foam cells, they become part of the disease's physical bulk. Although their indiscriminate targeting would interfere with normal homeostasis and immunity, and is therefore therapeutically nonviable, the discovery that monocytes are comprised of distinct subsets in human, mouse and other mammals suggests specialization of function, and has stimulated interest in approaches that discriminate between harmful and beneficial subsets. In this proposal we will test the hypothesis that monocyte subsets contribute differentially to atherogenesis and can be targeted selectively to image and treat the disease. Experiments will utilize classical cell biology tools, molecular profiling, and recently developed in vivo molecular imaging and therapeutic technologies that permit to interrogate monocyte biology at multiple resolutions, from the whole animal to a single cell. The project will interact closely with local imaging, immunology and cardiovascular groups and with outside collaborators. The ability to target monocyte subsets would advance our understanding of atherogenesis, and may allow us to evaluate drugs designed to selectively inhibit monocyte subset recruitment or function, and to stratify patients at risk for developing complications of atherosclerosis such as myocardial infarction or stroke. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a chronic disease and a leading cause of heart attack and stroke. Immune cells called monocytes are important in how the disease progresses. This grant will investigate whether it's possible to treat atherosclerosis by targeting these cells.