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Efferocytosis in CVD & Inflammation

CVD中的胞吞作用

基本信息

批准号：
8499393
负责人：
Edward Benjamin Thorp
金额：
$ 23.63万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-07-31
项目状态：
已结题

项目摘要

Atherothrombotic vascular disease and Ml are the leading cause of sudden death and disability worldwide. This necessitates the development of new strategies towards slowing progression of atherosclerotic and CVD disease. According to recent findings in experimental animals and humans, a major feature of advanced, rupture-prone atherosclerotic plaque is defective clearance of apoptotic cells. Apoptotic cell death, in the absence of efficient phagocytic clearance (efferocytosis), promotes post-apoptotic necrosis, which contributes to inflammation and plaque disruption. Surprisingly, though numerous candidates have been implicated, the key factors that lead to defective efferocytosis in-vivo have yet to be elucidated. We have recently discovered that deficiency of the cell surface receptor MERTK, reduces efferocytosis in murine lesions and promotes key features of plaque vulnerability, namely necrotic core expansion. Interestingly, preliminary data also suggest that advanced coronary disease in humans coincides with proteolytic degradation of MERTK. To determine if MERTK proteolysis contributes to plaque destabilization, we have engineered a cleavage-resistant MERTK. In-vitro, MERTK proteolysis is driven by inflammation. In-vivo, an "inflammatory" Ly6C-HI monocyte subset is recruited to atherosclerotic lesions and post myocardial infarcts and differentiate into macrophage phagocytes. In collaborative work, we have found that Ly6C-HI monocytes differentiate into a subset of phagocytes with poor in-vitro efferocytosis efficiency. We hypothesize that plaque vulnerability and maladaptive post Ml repair is promoted by inflammatory phagocyte subsets with reduced functional MERTK and poor efferocytosis efficiency. We will elucidate the molecular mechanisms that regulate efferocytosis efficiency of phagocyte subpopulations both in vitro and in vivo. This overall concept presents an opportunity for novel therapeutic strategies directed against progression of inflammation and CVD, namely through the elucidation of mechanisms that control in-vivo efferocytosis efficiency and modalities aimed at restoration and augmentation of defective efferocytosis.

动脉粥样硬化血栓性血管疾病和MI是全球猝死和残疾的主要原因。这就需要开发新的策略来减缓动脉粥样硬化的进展，心血管疾病。根据最近在实验动物和人类身上的发现，晚期、易破裂的动脉粥样硬化斑块是凋亡细胞的清除缺陷。凋亡细胞在缺乏有效吞噬清除（吞噬作用）的情况下，死亡促进凋亡后坏死，这会导致炎症和斑块破裂。令人惊讶的是，尽管许多候选人虽然已经发现了这些问题，但是导致体内缺陷性红细胞增多症的关键因素还有待阐明。我们最近发现，细胞表面受体MERTK的缺陷，减少了小鼠中的红细胞增多症，病变和促进斑块脆弱性的关键特征，即坏死核心扩张。有趣的是，初步数据还表明，人类的晚期冠状动脉疾病与蛋白水解 MERTK降解。为了确定MERTK蛋白水解是否有助于斑块不稳定，我们改造了一种抗切割的MERTK在体外，MERTK蛋白水解由炎症驱动。体内， “炎性”Ly 6C-HI单核细胞亚群被募集到动脉粥样硬化病变和心肌梗死后并分化成巨噬细胞。在合作工作中，我们发现Ly 6C-HI 单核细胞分化成体外吞噬作用效率差的吞噬细胞亚群。我们假设M1修复后斑块脆弱性和适应不良是由炎性吞噬细胞促进的具有降低的功能性MERTK和差的胞饮效率的亚群。我们将阐明在体外和体内调节吞噬细胞亚群的吞噬作用效率的机制。这总体概念为针对疾病进展的新治疗策略提供了机会。炎症和心血管疾病，即通过阐明控制体内细胞发热的机制旨在恢复和增强有缺陷的红细胞增多症的效率和方式。