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.

动脉粥样硬化性血管疾病和MI是全世界猝死和残疾的主要原因。这就需要制定新的策略来减缓动脉粥样硬化和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中的发现，一个主要特征晚期、易破裂的动脉粥样硬化斑块是凋亡细胞清除有缺陷的。凋亡细胞在缺乏有效的吞噬清除（胞吞作用）的情况下，死亡会促进凋亡后坏死，这会导致炎症和斑块破坏。令人惊讶的是，尽管许多候选人都受到牵连，导致体内胞吞作用缺陷的关键因素尚未阐明。我们最近发现细胞表面受体 MERTK 的缺陷会减少小鼠的胞吞作用损伤并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，人类晚期冠心病与蛋白水解作用同时发生。 MERTK 的降解。为了确定 MERTK 蛋白水解是否会导致斑块不稳定，我们有设计了一种抗裂解的 MERTK。在体外，MERTK 蛋白水解是由炎症驱动的。在体内， “炎症”Ly6C-HI 单核细胞亚群被募集到动脉粥样硬化病变和心肌梗塞后并分化为巨噬细胞吞噬细胞。在协同工作中，我们发现Ly6C-HI 单核细胞分化为吞噬细胞的子集，其体外胞吞作用效率较差。我们假设炎症吞噬细胞促进斑块脆弱性和ML修复后适应不良功能 MERTK 降低且胞吞效率较差的亚群。我们将阐明分子调节体外和体内吞噬细胞亚群的胞吞效率的机制。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CVD，即通过阐明控制体内胞吞作用的机制旨在恢复和增强有缺陷的胞吞作用的效率和方式。