Role of Fc Receptor in atherosclerotic plaque progression

描述(申请人提供)：心血管疾病是美国的主要死亡原因，大多数发病率和死亡率都是由斑块破裂引起的。每年约有15.7万人死于中风。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治疗方法。为此，我们比较了动脉内膜切除术获得的稳定斑块(股动脉)和不稳定斑块(颈动脉)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的斑块中升高。有趣的是，FC的组成部分是什么？受体信号通路，包括Fc？RI、Fc？R1a和Fc？RIII，在不稳定斑块中显著高于稳定斑块。用免疫复合体或C反应蛋白(连接Fc？R受体)孵育的人巨噬细胞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，可能导致斑块进展和/或不稳定。如果是真的，减少Fc？R信号的治疗可能为稳定易损斑块提供一种新的方法。然而，Fc？R在斑块进展和易损性中的作用尚未确定。这就是本应用程序的主题。三个特定的目标将检验Fc？R导致颈动脉斑块易损性和/或发展的假设。目的：1)不表达或全部表达活化Fc？R的载脂蛋白E-/-小鼠的斑块稳定性将使用6种斑块易损性的标准指标进行量化，包括脂质堆积、斑块内出血、斑块破裂和薄帽纤维动脉粥样硬化瘤；目的2)将测定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；目的3)利用无创小动物超声生物显微镜纵向追踪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/或易损性的问题，并确立该模型作为人类颈动脉斑块病理的代表的有效性。这些结果将为后续的研究提供理论基础，识别Fc？R诱导的斑块不稳定基因，并评估下调这些基因对颈动脉斑块进展和易损性的影响。项目简介：在美国，每分钟有3人死于心脏病，其中大部分死于斑块破裂。我们的数据表明，FCR信号参与了不稳定斑块的发展。这项研究将确定Fc？R在斑块进展和破裂中的作用，并为减少心脏病发作和中风提供新的靶点。

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.