Role of Macrophage Activation in Carotid Plaque Instability

描述(申请人提供)：心血管疾病是美国的主要死亡原因，大部分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、FcgR11a和Fc？RIII在不稳定斑块中显著高于稳定斑块。人巨噬细胞与免疫复合物或C反应蛋白孵育的体外研究(连接Fc？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，可能导致斑块进展和/或不稳定。如果是真的，降低FC的治疗方法是什么？R信号可能为稳定易损斑块提供一种新的途径。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。我们可以通过植入不同几何形状的狭窄袖带或管型，在易患动脉粥样硬化的载脂蛋白E-/-小鼠身上诱导稳定和不稳定的颈动脉斑块。将管型和袖带植入表达激活或抑制Fc？R的载脂蛋白E-/-小鼠，利用这两种模型对表达不同类型Fc？R，我们将检验激活Fc？R参与颈动脉粥样硬化斑块形成和/或稳定性的假设。I)Fc？R表达对稳定斑块和不稳定斑块发展的影响将通过超声生物显微镜来确定。Ii)组织学将被用来确定FC的效果？R表达对斑块稳定性的影响。3)定量RT-PCR将用于检测表达不同Fc？R补体的小鼠斑块不稳定基因的表达。这一应用为卒中的研究提供了一条新的途径。成功的完成将确定在稳定斑块和不稳定斑块中差异表达的基因，以及激活和抑制Fc？R对该表达的作用。这些结果将为R01提供足够的初步数据，旨在使用病毒转导来选择性地修改“斑块不稳定基因”，以努力稳定脆弱的斑块。与公共卫生相关：在美国，每分钟有3人死于心脏病，其中大部分是斑块破裂造成的。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FcgR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 much 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, FcgRlla, 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? 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. We can induce stable and unstable carotid plaques in atherosclerosis-prone Apo E-/- mice by implanting constrictive cuffs or casts with different geometries. Cast and cuffs will be implanted in Apo E-/- mice expressing activating or inhibitory Fc?R. Using these two models on mice expressing different types of Fc? R , we will test the hypothesis that activating Fc?R are involved in the formation and/or stability of carotid atherosclerotic plaques. I) The effect of Fc?R expression on stable and unstable plaque development will be determined using ultrasound biomicroscopy. II) Histology will be used to determine the effect of Fc? R expression on plaque stability. III) Quantitivative RT-PCR will be used to determine the expression of plaque instability genes in mice expressing different complements of Fc?R. This application details a comprehensive and novel approach to the study of stroke. Successful completion will identify genes that are differentially expressed in stable vs unstable plaques and the role of the activating and inhibitory Fc?R on that expression. The results will provide sufficient preliminary data for an R01 aimed at using viral transduction to selectively modify "plaque instability genes" in an effort to stabilize vulnerable plaques. PUBLIC HEALTH RELEVANCE: 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 FcgR in plaque progression and rupture and provide novel targets for reducing heart attack and stroke.