Neutrophils in atherosclerotic plaque destabilization

心血管疾病（CVD）的主要原因是动脉粥样硬化，动脉壁的慢性炎症导致明确斑块的形成。纤维帽变薄和坏死核心生长是斑块不稳定的主要诱因，并增加斑块破裂的风险。现有的斑块不稳定机制研究主要以巨噬细胞为中心，将其转化为临床研究在很大程度上失败了，而中性粒细胞指示的炎症在斑块不稳定中的作用被忽视了。在这里，我的目的是剖析中性粒细胞对斑块不稳定的机制贡献，从而确定新的治疗靶点并开辟创新的治疗机会。具体来说，我将(I)研究中性粒细胞在动脉粥样硬化斑块不稳定中的总体重要性，（ii）确定将中性粒细胞吸引到晚期动脉粥样硬化病变的趋化引导信号。同时，（iii）将仔细研究中性粒细胞驱动的斑块不稳定机制，包括中性粒细胞衍生的蛋白酶和中性粒细胞携带的警报。从长远来看，这些研究的发现应该转化为基于纳米医学的方法来干扰中性粒细胞指示的斑块减弱。因此，在目标（iv）中，我将测试基于抗体的递送策略。因此，该项目将对了解斑块不稳定的机制做出重大贡献，并提供新的治疗靶点。

The primary cause for cardiovascular disease (CVD) is atherosclerosis, a chronic inflammation of the arterial wall resulting in formation of defined plaques. Fibrous cap thinning and necrotic core growth are major inducers of plaque instability and increase the risk of plaque rupture. Existing mechanistic studies on plaque destabilization have mainly been macrophage-centric and translating these into the clinic has largely failed, while the role of neutrophil-instructed inflammation in plaque instability has been neglected. Here, I aim at dissecting the mechanistic contribution of neutrophils to plaque destabilization thus identifying novel therapeutic targets and opening up innovative therapeutic opportunities. Specifically, I will (i) study the overall importance of neutrophils in atherosclerotic plaque destabilization and (ii) identify chemotactic guidance signals attracting neutrophils to advanced atherosclerotic lesions. In parallel, (iii) mechanisms of neutrophil-driven plaque destabilization including neutrophil-derived proteases and neutrophil-borne alarmins will be scrutinized. In the long-run, findings from these studies shall be translated into nanomedicine-based approaches to interfere with neutrophil-instructed plaque weakening. In aim (iv) I will hence test an antibody-based delivery strategy. Thus, the project will make a major contribution to the understanding of mechanisms underlying plaque destabilization and provide novel therapeutic targets.