Efferocytosis in CVD & Inflammation

描述(申请人提供)：动脉粥样硬化性血栓性血管疾病是全世界导致猝死和残疾的主要原因。尽管降脂策略显著降低了心血管发病率和死亡率，但心血管事件的残余风险仍然很高。这就需要制定替代和补充的战略，以减缓动脉粥样硬化性疾病的进展。根据最近在实验动物和人类中的发现，晚期、易破裂的动脉粥样硬化斑块的一个主要特征是对凋亡细胞的缺陷清除。在缺乏有效的吞噬细胞清除的情况下，凋亡性细胞死亡会促进凋亡后的坏死，从而导致炎症和斑块破坏。令人惊讶的是，虽然已经有许多候选人被牵连，但导致体内有缺陷的铁粒细胞增多的关键因素还没有被阐明。我们最近发现，细胞表面受体MerTK的缺乏，减少了小鼠皮损中的泡沫化细胞数，并促进了斑块易损性的关键特征，即坏死性核心扩张。有趣的是，初步数据还表明，人类晚期冠状动脉疾病与MerTK的蛋白分解降解是一致的。为了确定MerTK蛋白分解是否导致斑块不稳定，我们将设计一只小鼠来表达抗切割MerTK，并随后测量斑块坏死。在体外，MerTK的蛋白分解是由炎症驱动的。在体内，一个“炎性的”Ly6C-hi单核细胞亚群被招募到动脉粥样硬化病变中，并分化为巨噬细胞吞噬细胞。在合作工作中，我们发现Ly6C-hi单核细胞分化为吞噬细胞亚群，体外泡泡细胞效率较低。我们假设斑块易损性是由于炎性吞噬细胞亚群功能MerTK降低和泡泡细胞效率低下所致。我们将阐明在体外和体内调节吞噬细胞亚群吞噬效率的分子机制。这一总体概念为针对炎症进展和动脉粥样硬化血栓形成的新的治疗策略提供了机会，即通过阐明控制体内泡细胞效率的机制和旨在修复和增强缺陷泡细胞的方式。相关性(见说明书)：泡腾细胞体内调节的研究，虽然仍处于非常早期的发展阶段，但可能为许多慢性炎症性疾病的治疗提供基础。这些研究有可能阐明新的治疗靶点，既可以针对炎性细胞凋亡的积累，也可以针对晚期斑块的进展，即通过修复和增强有缺陷的效应。

DESCRIPTION (provided by applicant): Atherothrombotic vascular disease is the leading cause of sudden death and disability worldwide. Though lipid-lowering strategies have significantly reduced cardiovascular morbidity and mortality, the residual risk for cardiovascular events remains high. This necessitates the development of alterative and complementary strategies towards slowing progression of atherosclerotic 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 phagocyte 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 efferocytosls 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 will engineer a mouse to expresses cleavage-resistant Mertk and subsequently measure plaque necrosis. In-vitro, Mertk proteolysis is driven by inflammation. In-vivo, an "inflammatory" Ly6C-hi monocyte subset is recruited to atherosclerotic lesions and differentiates into macrophage phagocytes. In collaborative work, we have found that Ly6C-hi monocytes differentiate into a subset of phagocytes with poor in-vitro efferocytosls efficiency. We hypothesize that plaque vulnerability is promoted by inflammatory phagocyte subsets with reduced functional Mertk and poor efferocytosls 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 atherothrombosis, namely through the elucidation of mechanisms that control in-vivo efferocytosls efficiency and modalities aimed at restoration and augmentation of defective efferocytosls. RELEVANCE (See instructions): The study of in-vivo regulation of efferocytosls, although still at a very early stage of development, may provide the basis for therapy in numerous chronic inflammatory disorders. These studies have the potential to elucidate novel therapeutic targets that can be directed against both the accumulation of inflammatory apoptotic cells and the progression of advanced plaques, namely, through restoration and enhancement of defective effemnvtoRls.