Role of Fc Receptor in atherosclerotic plaque progression

Fc 受体在动脉粥样硬化斑块进展中的作用

• 批准号: 7669103
• 负责人: Michelle R Lennartz
• 金额: $ 17.85万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669103
• 关键词: Accounting; Animal Model; Animals; Antigen-Antibody Complex; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; C-reactive protein; Cardiovascular Diseases; Carotid Artery Plaques; Cause of Death; Cessation of life; Data; Development; Diet; Down-Regulation; Endarterectomy; Extracellular Matrix; Fatty acid glycerol esters; Fc Receptor; Gene Expression; Gene Proteins; Generations; Genes; Heart Diseases; Hemorrhage; Human; In Vitro; Incubated; Individual; Investigation; Ligands; Lipids; Longitudinal Studies; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Messenger RNA; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Myocardial Infarction; Pathologist; Pathology; Pattern; Phenotype; Production; Proteins; Publishing; Receptor Signaling; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Rupture; Signal Pathway; Signal Transduction; Stenosis; Stroke; TNF gene; Techniques; Technology; Testing; Time; Tissues; Transgenic Organisms; Ultrasonographic Biomicroscopy; United States; Up-Regulation; Western Blotting; capsule; feeding; genetic regulatory protein; macrophage; mortality; novel; novel strategies; protein expression; receptor; receptor expression; receptor-mediated signaling; standard measure; therapy design

DESCRIPTION (provided by applicant): Cardiovascular disease is the major cause of death in the United States with most of the morbidity and mortality resulting from plaque rupture. Strokes account for approximately 157,000 of those deaths each year. As the majority of strokes result from plaque rupture, elucidating the differences between vulnerable and stable plaques will aid in the design of therapies to stabilize vulnerable plaques. To this end, we have compared the expression of 21 genes in stable (femoral) and unstable (carotid) plaques obtained from endarterectomy. Not surprisingly, genes involved in the breakdown of the extracellular matrix were elevated in the unstable plaques. Interestingly, components of the Fc? receptor signaling pathway, including Fc?RI, Fc?Rlla, and Fc?RIII are dramatically higher in unstable compared to stable plaques. In vitro studies using human macrophages incubated with immune complexes or C reactive protein (to ligate Fc?R receptors) recapitulated the expression profile of the unstable plaque tissue. These data suggest that the Fc?R- mediated signaling network is upregulated in unstable plaques and may contribute to plaque progression and/or instability. If true, treatments to decrease Fc?R signaling may provide a novel approach for stabilizing vulnerable plaques. However, the role of Fc?R in plaque progression and vulnerability has yet to be determined. That is the subject of this application. Three specific aims will test the hypothesis that Fc?R contribute to the vulnerability and/or development of carotid plaques. Aim I) Plaque stability in Apo E -/- mice expressing none or all of the activating Fc?R will be quantified using 6 standard measures of plaque vulnerability, including lipid accumulation, intraplaque hemorrhage, plaque rupture, and thin cap fibroatheroma, Aim II) the effect of Fc?R expression on gene expression profiles will be determined and compared to those of stable and unstable human plaques, and Aim III) the effect of Fc?R expression on plaque development will be followed longitudinally using non-invasive, small animal ultrasound biomicroscopy. Completion of these studies will resolve the question of the involvement of Fc?R in plaque progression and/or vulnerability and establish the validity of the model as representative of human carotid plaque pathology. The results will provide the rationale for subsequent studies identifying Fc?R induced plaque instability genes and assessing the effects of downregulating such genes on carotid plaque progression and vulnerability. Project Narrative: In the United State, 3 people die from heart disease every minute with plaque rupture contributing to the majority of those deaths. Our data suggest that FcR signaling in involved in the development of unstable plaques. This research will determine the role of Fc?R in plaque progression and rupture and provide novel targets for reducing heart attack and stroke.

描述（由申请人提供）：心血管疾病是美国主要的死亡原因，其中大部分发病率和死亡率是由斑块破裂引起的。每年约有 157,000 人死于中风。由于大多数中风是由斑块破裂引起的，阐明易损斑块和稳定斑块之间的差异将有助于设计稳定易损斑块的疗法。为此，我们比较了从动脉内膜切除术获得的稳定（股骨）和不稳定（颈动脉）斑块中 21 个基因的表达。毫不奇怪，参与细胞外基质分解的基因在不稳定斑块中升高。有趣的是，Fc 的组成部分？与稳定斑块相比，不稳定斑块中的受体信号通路（包括 Fc?RI、Fc?Rlla 和 Fc?RIII）显着升高。使用与免疫复合物或 C 反应蛋白（连接 Fc?R 受体）孵育的人巨噬细胞进行的体外研究概括了不稳定斑块组织的表达谱。这些数据表明Fc?R介导的信号网络在不稳定斑块中上调，并且可能导致斑块进展和/或不稳定。如果属实，减少 Fc?R 信号传导的治疗可能会提供一种稳定易损斑块的新方法。然而，Fc?R 在斑块进展和脆弱性中的作用尚未确定。这就是本申请的主题。三个具体目标将检验 Fc?R 导致颈动脉斑块脆弱性和/或发展的假设。目标 I) 不表达或全部表达活化 Fc?R 的 Apo E -/- 小鼠中的斑块稳定性将使用斑块脆弱性的 6 种标准测量进行量化，包括脂质积累、斑块内出血、斑块破裂和薄帽纤维粥样硬化，目标 II) 将确定 Fc?R 表达对基因表达谱的影响，并与稳定和不稳定的人类斑块进行比较，以及 目标 III) 将使用非侵入性小动物超声生物显微镜纵向跟踪 Fc?R 表达对斑块发展的影响。这些研究的完成将解决 Fc?R 参与斑块进展和/或脆弱性的问题，并确定该模型作为人类颈动脉斑块病理学代表的有效性。该结果将为后续研究识别 Fc?R 诱导斑块不稳定基因并评估下调此类基因对颈动脉斑块进展和脆弱性的影响提供依据。项目叙述：在美国，每分钟有 3 人死于心脏病，其中大部分死亡是斑块破裂造成的。我们的数据表明 FcR 信号传导参与不稳定斑块的发展。这项研究将确定 Fc?R 在斑块进展和破裂中的作用，并为减少心脏病和中风提供新的靶标。