Role of Macrophage Activation in Carotid Plaque Instability

描述（由申请人提供）：心血管疾病是美国死亡的主要原因，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21个基因在动脉内膜切除术后获得的稳定（股骨）和不稳定（颈动脉）斑块中的表达。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？受体信号通路，包括Fc？RI、fcgrla和Fc？与稳定斑块相比，不稳定斑块中的RIII明显更高。人巨噬细胞与免疫复合物或C反应蛋白(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。如果是这样，降低Fc的治疗方法？R信号可能为稳定易损斑块提供新的途径。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收缩袖带或铸型，在易发生动脉粥样硬化的载脂蛋白E-/-小鼠中诱导稳定和不稳定的颈动脉斑块。石膏和袖口将植入表达激活或抑制Fc?R的Apo E-/-小鼠。将这两种模型用于表达不同类型Fc？R，我们将验证激活Fc？R参与颈动脉粥样硬化斑块的形成和/或稳定性。1) Fc？R在稳定和不稳定斑块发展中的表达将通过超声生物显微镜来确定。II)组织学将用于确定Fc？R表达对斑块稳定性的影响。III)定量RT-PCR将用于测定表达不同Fc?R补体小鼠斑块不稳定基因的表达。该应用程序详细介绍了一种全面而新颖的中风研究方法。成功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在这个表达式上。该结果将为R01提供足够的初步数据，该R01旨在利用病毒转导选择性地修饰“斑块不稳定基因”，以稳定易损斑块。公共卫生相关性：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形成。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.