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.

动脉瘤血栓性血管疾病和ML是全球猝死和残疾的主要原因。这有必要制定新策略来减缓动脉粥样硬化和 CVD疾病。根据实验动物和人类的最新发现，晚期，可破裂的动脉粥样硬化斑块是凋亡细胞的缺陷清除率。凋亡细胞在没有有效的吞噬清除率（肿瘤病）的情况下，死亡会促进凋亡后坏死，这有助于炎症和牙菌斑破坏。令人惊讶的是，尽管许多候选人有被暗示的是，导致体内肿瘤病缺陷的关键因素尚未阐明。我们最近发现细胞表面受体MERTK缺乏，减少了鼠的肿瘤病病变和促进斑块脆弱性的关键特征，即坏死核心的扩张。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一致 Mertk的退化。为了确定MERTK蛋白水解是否有助于牙菌斑的稳定，我们有设计了一种抗切割的Mertk。体外，MERTK蛋白水解是由炎症驱动的。体内，一个 “炎症” LY6C-HI单核细胞子集被募集到动脉粥样硬化病变并在心肌梗塞后并分化为巨噬细胞的吞噬细胞。在协作工作中，我们发现Ly6c-hi 单核细胞分化为吞噬不良的吞噬细胞的子集。我们假设斑块脆弱性和适应不良后ML修复是通过炎症性吞噬细胞促进的功能性MERTK降低和衰减效率差的亚集。我们将阐明分子调节体外和体内吞噬细胞亚群体吞噬效率的机制。这总体概念为针对进步的新型治疗策略提供了一个机会炎症和CVD，即通过阐明控制体内肿瘤的机制旨在恢复和增强肿瘤有缺陷的效率和方式。