Critical Mediators of Inflammation Resolution and Immune Memory in Atherosclerosis

项目摘要 尽管医学取得了重大进展，但心血管疾病仍然是发病的主要原因 和死亡率。即使有积极的风险因素控制，近50%的患者患有 复发性心脏事件和这种“剩余风险”归因于过度炎症。 最近的研究表明，动脉粥样硬化的特征还在于 炎症消退。解决方案是由专门的生产调节 促分解脂质介质（SPM）和凋亡细胞的有效清除（胞浆细胞增多症） 从组织。晚期动脉粥样硬化斑块有更多的凋亡细胞， 坏死核心和促炎介质失衡：与 早期病变，所有这些都表明未能解决。提高分辨率的策略， 打破慢性炎症循环，促进斑块稳定。因此， 介导该过程的新靶点是至关重要的。我们的初步数据显示 确定了Ca 2 +/钙调蛋白依赖性蛋白激酶IV（CaMK 4）作为两者的中心调节因子， 炎症和消退。独特的是，CaMK 4似乎在细胞凋亡中发挥重要作用。 巨噬细胞先天免疫记忆的发展，这增强了它们的前 炎症反应致动脉粥样硬化刺激。因此，我们假设CaMK 4是一种 免疫记忆的关键介质，免疫训练通过 CaMK 4依赖机制。我们将通过以下目标来检验我们的假设： 具体目标1将检验髓样CaMK 4损害消退作为机制的假设 从而促进动脉粥样硬化的进展。 具体目标2将探讨CaMK 4促进oxLDL训练的机制， 骨髓祖细胞和巨噬细胞，以增加它们的炎性细胞因子 生产 特异性目标3将检验在晚期动脉粥样硬化中靶向CaMK 4的假设， 促进牙菌斑消退。

PROJECT SUMMARY Despite major medical advances, cardiovascular disease remains the major cause of morbidity and mortality worldwide. Even with aggressive risk factor control, nearly 50% of patients suffer recurrent cardiac events and this “residual risk” has been attributed to excessive inflammation. Recent work has demonstrated that atherosclerosis is also characterized by the failure of inflammation resolution. The resolution program is regulated by the production of specialized pro-resolving lipid mediators (SPMs) and the efficient clearance of apoptotic cells (efferocytosis) from tissue. Advanced atherosclerotic plaques have higher numbers of apoptotic cells, larger necrotic cores, and an imbalance of pro-inflammatory:pro-resolving mediators compared with early lesions, all of which are suggestive of failed resolution. Strategies that boost resolution and break the cycle of chronic inflammation promote plaque stability. Therefore, the identification of novel targets that mediate this process is of critical importance. Our preliminary data have identified Ca2+/Calmodulin-Dependent Protein Kinase IV (CaMK4) as a central regulator of both inflammation and resolution. Uniquely, CaMK4 appears to play an important role in the development of innate immune memory in macrophages, which enhances their pro- inflammatory responses to atherogenic stimuli. Therefore, we hypothesize that CaMK4 is a critical mediator of immune memory and that immune training impairs resolution through a CaMK4-dependent mechanism. We will test our hypothesis through the following aims: Specific Aim 1 will test the hypothesis that myeloid-CaMK4 impairs resolution as a mechanism by which it promotes atheroprogression. Specific Aim 2 will explore the mechanism by which CaMK4 promotes oxLDL training of myeloid progenitors and macrophages in order to augment their inflammatory cytokine production. Specific Aim 3 will test the hypothesis that targeting CaMK4 in advanced atherosclerosis can promote regression of plaque.