Efferocytosis in CVD & Inflammation

CVD中的胞吞作用

基本信息

批准号：
7714046
负责人：
Edward Benjamin Thorp
金额：
$ 9万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7714046
关键词：
Acute Acute myocardial infarction Animals Apoptosis Apoptotic Arterial Fatty Streak Atherosclerosis Autoimmunity Automobile Driving Blood Vessels Cardiovascular Pathology Cardiovascular system Carotid Artery Ulcerating Plaque Cell Death Cell Surface Receptors Cells Chronic Cleaved cell Clinical Collaborations Complement Coronary heart disease Data Development Disease Engineering Event Failure Goals Human ITGAX gene In Vitro Inflammation Inflammatory Institutes Instruction Knock-out Knockout Mice Lead Lesion Link Lipids Maryland Measures Modality Modeling Molecular Morbidity - disease rate Mus Necrosis New York Operative Surgical Procedures Pathway interactions Peptide Hydrolases Peripheral Phagocytes Population Proteolysis Recruitment Activity Regulation Residual state Resistance Resolution Retinal Cone Rupture Staging Stimulus Sudden Death Systemic Lupus Erythematosus Testing Thrombosis Tissues Translating Universities Vascular Diseases Work atherothrombosis base cardiovascular risk factor disability in vivo macrophage monocyte mortality new therapeutic target novel therapeutics receptor restoration

项目摘要

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.

描述（由申请人提供）：动脉粥样硬化血管疾病是全球猝死和残疾的主要原因。尽管降低脂质的策略显着降低了心血管发病率和死亡率，但心血管事件的残留风险仍然很高。这需要开发改变动脉粥样硬化疾病进展的改变和互补策略。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的主要特征是凋亡细胞的有缺陷。凋亡细胞死亡在没有有效的吞噬细胞清除率（肿瘤病）的情况下促进了凋亡后坏死，这有助于炎症和斑块破坏。令人惊讶的是，尽管已经涉及了许多候选人，但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的缺乏，减少鼠病变中的for胞胞菌，并促进斑块脆弱性的关键特征，即坏死的核心膨胀。有趣的是，初步数据还表明，人类的晚期冠状动脉疾病与MERTK的蛋白水解降解相吻合。为了确定MERTK蛋白水解是否有助于牙菌斑的破坏性，我们将设计小鼠以表达抗裂解的MERTK并随后测量斑块坏死。体外，MERTK蛋白水解是由炎症驱动的。体内，将“炎症” Ly6c-Hi单核细胞子集募集到动脉粥样硬化病变中，并区分为巨噬细胞吞噬细胞。在协作工作中，我们发现LY6C-HI单核细胞分化为吞噬细胞的子集，其体外效率效率较差。我们假设斑块脆弱性是由功能性MERTK降低和效率低下的炎症性吞噬细胞子集促进的。我们将阐明在体外和体内调节吞噬细胞亚群的传染性效率的分子机制。这个总体概念为针对炎症和动脉粥样硬化进展的新型治疗策略提供了一个机会，即通过阐明控制体内效率的机制，旨在恢复和增强有缺陷的efferocytosls。相关性（请参阅说明）：efferocytosls的体内调节的研究虽然仍处于发展的早期阶段，但可能为多种慢性炎性疾病的治疗提供了基础。这些研究具有阐明新型治疗靶标的潜力，可以针对炎症性凋亡细胞的积累和晚期斑块的进展，即通过恢复和增强有缺陷的丧失性。