Role of Fc Receptor in atherosclerotic plaque progression

描述（由申请方提供）：心血管疾病是美国的主要死因，大部分发病率和死亡率由斑块破裂引起。中风每年约占这些死亡人数的157 000人。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21个基因的表达稳定（股动脉）和不稳定（颈动脉）斑块动脉内膜切除术。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？受体信号通路，包括Fc？RI，Fc？Rlla和Fc？与稳定斑块相比，不稳定斑块中的RIII显著更高。在体外研究中，使用与免疫复合物或C反应蛋白孵育的人巨噬细胞（连接Fc？R受体）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，并可能导致斑块进展和/或不稳定。如果是真的，治疗，以减少Fc？R信号可能为稳定易损斑块提供了一种新的方法。然而，Fc的作用？R在斑块进展和易损性中的作用尚未确定。这就是本申请的主题。三个具体的目标将测试的假设，Fc？R促进颈动脉斑块的易损性和/或发展。目的I）载脂蛋白E -/-小鼠中的空斑稳定性，所述载脂蛋白E-/-小鼠不表达或表达所有活化Fc？R将使用斑块易损性的6个标准测量来量化，包括脂质积聚、斑块内出血、斑块破裂和薄帽纤维粥样硬化。R表达的基因表达谱将被确定和比较的稳定和不稳定的人类斑块，和目的III）Fc？将使用非侵入性小动物超声生物显微镜纵向跟踪斑块发展中的R表达。这些研究完成后，财务委员会是否参与的问题便可解决？R在斑块进展和/或易损性中的作用，并建立该模型作为人类颈动脉斑块病理学代表的有效性。这些结果将为随后的研究确定Fc？诱导斑块不稳定基因，并评估下调这些基因对颈动脉斑块进展和易损性的影响。项目叙述：在美国，每分钟有3人死于心脏病，其中大多数死亡是由斑块破裂造成的。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的作用？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了新的靶点。

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.