Role of Macrophage Activation in Carotid Plaque Instability

描述（由申请人提供）：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、FcgRIIa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？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。我们可以通过植入不同几何形状的收缩套囊或管型在易患动脉粥样硬化的Apo E-/-小鼠中诱导稳定和不稳定的颈动脉斑块。铸件和袖带将植入表达激活或抑制性Fc？R.使用这两种模型对小鼠表达不同类型的Fc？R，我们将测试的假设，激活Fc？R参与颈动脉粥样硬化斑块的形成和/或稳定。（一）Fc的作用？将使用超声生物显微镜测定稳定和不稳定斑块发展中的R表达。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将用于确定表达不同Fc互补物的小鼠中斑块不稳定性基因的表达。R.本申请详细介绍了一种全面而新颖的中风研究方法。成功完成将确定差异表达的基因在稳定与不稳定的斑块和激活和抑制Fc？R这个表情。这些结果将为R 01提供足够的初步数据，该R 01旨在使用病毒转导来选择性地修饰“斑块不稳定基因”，以稳定脆弱的斑块。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.