Role of Fc gamma receptors in atherosclerosis

Fc γ 受体在动脉粥样硬化中的作用

基本信息

批准号：
8277323
负责人：
SHANMUGAM NAGARAJAN
金额：
$ 36.98万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8277323
关键词：
Address Animal Model Animals Antibodies Antibody Formation Antigen Presentation Antigen-Antibody Complex Apolipoprotein E Arterial Fatty Streak Atherosclerosis Attenuated Autoantibodies Autoimmune Responses B-Lymphocytes Binding Blood Vessels Bone Marrow CD36 gene Cardiovascular Diseases Cause of Death Cell physiology Cells Chronic Coronary artery Country Dendritic Cells Dendritic cell activation Deposition Development Disease Endothelial Cells Event FCGR3B gene Foam Cells Foundations Future Generations Genetic Polymorphism Goals Health Hematopoietic Human Hyperlipidemia IgG Receptors Immune Immunoglobulin G In Vitro Individual Inflammation Inflammatory Inflammatory Response Injury Knockout Mice Laboratories Lead Lesion Lipids Low-Density Lipoproteins Mediating Molecular Mus Pathogenesis Patients Phagocytosis Play Predisposition Process Property Regulation Risk Factors Role Signal Transduction Smooth Muscle T-Lymphocyte Therapeutic Tissues Vascular Endothelial Cell Vascular Endothelium antibody-dependent cell cytotoxicity atherogenesis base cell type cytokine design in vivo low density lipoprotein inhibitor macrophage monocyte mouse model novel oxidized low density lipoprotein particle prevent receptor research study scavenger receptor therapeutic development tool uptake

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory process of the vascular endothelium that leads to cardiovascular disease. Generation of oxidized form of LDL (oxLDL) and its uptake by macrophages is an early event in the atherosclerosis. OxLDL also induces an autoimmune response as evidenced by the presence of antibody (IgG) against oxLDL and oxLDL-immune complex (oxLDL-IC) in atherosclerotic lesions in patients and animal model. The titer of autoantibodies against oxLDL is correlated with the progression of atherosclerosis in humans and in the hyperlipidemic mouse model. Therefore, oxLDL-IC could be involved in the inflammatory processes leading to the initiation and progression of atherosclerosis. We have shown that human monocytes adhere to oxLDL-IC coated endothelial cells in vitro and release inflammatory cytokines. This interaction is mediated through a group of cellular receptors called Fc gamma receptors (Fc?R), which bind immune complexes and play a major role in IC-mediated tissue injury in chronic inflammatory disease involving autoantibodies. Interaction of oxLDL-IC with Fc?Rs containing activation motif could initiate an inflammatory response while interaction with Fc?R containing the inhibitory receptor will dampen the inflammatory process. However, the role of Fc?R in initiation and progression of atherosclerosis is not known. We have generated double knock out mice lacking the activating or inhibitory Fc?R, in atherosclerosis prone apoE-/- mice, providing us tools to study the role of Fc?R during atherosclerosis. We have also observed that in addition to its interaction with IC, mouse CD16, a Fc?R can bind oxLDL directly and could have scavenger receptor like activity. Therefore in this proposal we will, (i) determine the role of activating Fc?R during atherosclerosis in vivo, (ii) delineate molecular mechanisms contributing to the attenuated lesions in the activating Fc?R deficient mice, (iii) determine the role of inhibitory Fc?R during atherosclerosis in vivo, and (iv) characterize the SR-like activity of mouse CD16 and determine its functional implications. Completion of this proposed study will significantly advance our understanding the role of Fc?Rs in the progression of atherosclerosis. Further, Our findings would allow for future development of therapeutics to block Fc?R-mediated inflammation with the goal of blocking or preventing the progression of atherosclerosis. PUBLIC HEALTH RELEVANCE: Atherosclerosis remains the leading cause of death in the USA and other Western countries. Completion of this proposed study will significantly advance our understanding the role of Fc?Rs in the lesion development during atherosclerosis. Further, it could allow for designing therapeutics by inhibiting atherogenesis via targeting activating and/or inhibitory Fc?Rs.

描述（由申请人提供）：动脉粥样硬化是导致心血管疾病的血管内皮的慢性炎症过程。 LDL（OXLDL）的氧化形式的产生及其巨噬细胞的吸收是动脉粥样硬化的早期事件。 OXLDL还诱导了自身免疫反应，这是由患者和动物模型中动脉粥样硬化病变中针对OXLDL和OXLDL-rimmune复合物（OXLDL-IC）的抗体（IgG）的存在所证明的。针对OXLDL的自身抗体的滴度与人类和高脂症小鼠模型中动脉粥样硬化的进展相关。因此，OXLDL-IC可能参与导致动脉粥样硬化起步和进展的炎症过程。我们已经表明，人的单核细胞在体外粘附于Oxldl-IC涂层的内皮细胞并释放炎症细胞因子。这种相互作用是通过一组称为FC伽马受体（FC？r）的细胞受体介导的，它们结合免疫复合物并在涉及自身抗体的慢性炎症性疾病中IC介导的组织损伤中起主要作用。 OXLDL-IC与含有活化基序的FC？RS的相互作用可以引发炎症反应，而与含有抑制性受体的FC？R相互作用会抑制炎症过程。但是，FC？r在动脉粥样硬化的启动和进展中的作用尚不清楚。我们已经产生了双重击倒小鼠，缺乏激活或抑制性FC？r，在动脉粥样硬化容易apoE - / - 小鼠中，为我们提供了研究FC？r在动脉粥样硬化过程中的作用的工具。我们还观察到，除了它与IC相互作用外，小鼠CD16还可以直接结合OXLDL，并且可以具有清除剂受体类似活性。因此，在该提案中，（i）确定在体内动脉粥样硬化期间激活Fc？r的作用，（ii）描述的分子机制，导致促进fc r缺陷小鼠的衰减病变的损害（iii）确定抑制性fc的作用在cdivo和cdivo中的作用（IIV）（iiv）表征sr的作用（iiv）的作用（iiv）。含义。这项拟议的研究的完成将大大促进我们理解Fc？rs在动脉粥样硬化进展中的作用。此外，我们的发现将允许将来的治疗剂开发阻断FC介导的炎症，以阻止或防止动脉粥样硬化的进展。公共卫生相关性：在美国和其他西方国家，动脉粥样硬化仍然是死亡的主要原因。这项拟议的研究的完成将大大促进我们在动脉粥样硬化期间的病变发展中FC的作用。此外，它可以通过靶向激活和/或抑制性FC来抑制动脉粥样硬化来设计治疗剂。