Determinants of Regulatory Macrophage Function in Coronary Artery Disease

项目总结/摘要 炎症是冠状动脉疾病（CAD）的主要原因，该过程涉及血管内皮细胞的积聚。 冠状动脉内的斑块。这些斑块导致心脏病发作和慢性心脏病， 心肌供血不足，因此，它们解释了世界范围内发病率和死亡率高于任何 其他病理过程。 巨噬细胞是免疫系统的细胞，是CAD中这些斑块的中心成分。我们有 发现了决定巨噬细胞是否成为炎症的关键因素， 疾病，或调节，这可以减少疾病，并将确定是否这些中心因素之一， Skap 2控制斑块中从炎症状态到调节状态的转换。有清晰的认识 是什么决定了斑块中巨噬细胞的行为，我们渴望最终指出新的疗法， 使巨噬细胞更具调节性-阻止它们驱动炎症-而是诱导它们 愈合或稳定斑块，以减轻CAD的负担。 该项目在几个方面都具有创新性和影响力。首先，与之前的许多工作相反， 巨噬细胞系或体外衍生的细胞，它将确定关键巨噬细胞分子在这一开关中的作用 直接从斑块分离的巨噬细胞的炎症调节功能。二是因为 将发现转化为人类是至关重要的，它将测量这些基因的相同调节功能和作用。 来源于循环前体细胞的人巨噬细胞中的分子，所述循环前体细胞获自具有不同 程度的CAD，并将这些发现与人类斑块组成相关联。最后， 该项目将评估的调节功能是“红细胞增多症”，即通过 巨噬细胞，这一过程被认为是阻止斑块炎症的潜在关键决定因素，也是一个重要的因素。 未来的新治疗目标。

Project Summary / Abstract Inflammation is a major contributor to coronary artery disease (CAD), the process that involves build-up of plaques within the coronary arteries. These plaques result in heart attacks and chronic heart disease due to poor blood supply to the heart muscle, and thus they explain more worldwide morbidity and mortality than any other pathological process. Macrophages are cells of the immune system that are central components of these plaques in CAD. We have discovered critical factors that determine whether macrophages become inflammatory, associated with worse disease, or regulatory, which can reduce disease, and will define whether or not one of these central factors, Skap2, governs the switch from the inflammatory to the regulatory state in plaques. With a clear understanding of what determines macrophage behavior in the plaque, we aspire ultimately to point to new therapies that make macrophages more regulatory—stopping them from driving inflammation—and instead inducing them to heal or stabilize plaques in order to reduce the burden of CAD. This project is innovative and impactful in several ways. First, as opposed to much prior work done on macrophage cell lines or cells derived in vitro, it will define the role of key macrophage molecules in this switch from inflammatory to regulatory function in macrophages isolated directly from the plaque. Second, because translating finding to humans is paramount, it will measure the same regulatory functions and roles of these molecules in human macrophages derived from circulating precursor cells obtained from subjects with varying degrees of CAD, and correlate these findings with plaque composition in humans. Finally, one of the key regulatory functions the project will assess is “efferocytosis”, the clearing of inflammatory debris by macrophages, a process recognized as a potential key determinant of halting inflammation in the plaque and a new treatment target for the future.