CRP Biology and Vascular Disease

摘要 尽管C反应蛋白(CRP)已被证明具有很强的预测价值 未来的心血管疾病(CVD)，目前仍不清楚CRP是否是一种非特异性风险 CVD发病机制中的标志物或直接介体。尽管有很大的临床重要性 目前，我们缺乏合适的动物模型来研究其在CVD中的作用，因为小鼠是 不是研究C反应蛋白功能的合适动物模型。在这个修改后的应用程序中，我们有 成功生成肝脏特异性(全身)和血管特异性(局部)CRP 转基因兔子是因为兔子的心血管系统和CRP反应 与人类相似。有趣的是，我们的初步数据首次记录了 在肝脏特异的CRP转基因中，系统CRP的增加可以促进动脉粥样硬化 兔子。因此，这两个独特的crp转基因兔模型的可用性将提供 美国强大的工具来确定CRP是否参与了CVD的发病机制。在这份提案中， 我们将验证中心假设，即肝脏来源的CRP和血管来源的CRP都起作用 协同作用，通过激活血管形成最广泛的血管病变 血管损伤后血管内皮细胞的增殖和迁移。具体来说，我们 威尔1)。用新的方法确定C反应蛋白参与血管疾病的发病机制 转基因兔模型，2)。确定全身C反应蛋白与局部C反应蛋白的相对影响 C反应蛋白是体内血管病变形成的“血管病变”介质。 总体而言，这些研究将提供中介影响的明确特征 C反应蛋白在心血管疾病中的作用。我们的研究将对理解C反应蛋白产生深远的影响 血管疾病中的功能和CRP作为指导临床风险的生物标记物的充分利用 预防和治疗心血管疾病的评估和治疗策略。

Abstracts Although C-reactive protein (CRP) has been shown to have a strong predictive value for future cardiovascular disease (CVD), it is still unclear whether CRP is a non-specific risk marker or a direct mediator in the pathogenesis of CVD. Despite the great clinical importance of CRP, we currently lack an appropriate animal model to study its role in CVD since mouse is not an appropriate animal model to study CRP functions. In this revised application, we have successfully generated both liver-specific (systemic) and vascular-specific (local) CRP transgenic rabbits because rabbits have a cardiovascular system and CRP response that are similar to those of humans. Intriguingly, our preliminary data have documented for the first time that increased systemic CRP can promote atherosclerosis in liver-specific CRP transgenic rabbits. Thus, the availability of these two unique CRP transgenic rabbit models would provide us powerful tools to define whether CRP participates in pathogenesis of CVD. In this proposal, we will test the central hypothesis that both liver-derived CRP and vascular-derived CRP act synergistically to produce the most extensive vascular lesion formation by activating vascular smooth muscle cell proliferation and migration in response to vascular injury. Specifically, we will 1). Define that CRP participates in pathogenesis of vascular disease using novel transgenic rabbit models, and 2). Define the relative influence of systemic CRP versus local CRP as a "vasculopathic" mediator of vascular lesion formation in vivo. Overall, these studies will provide a definitive characterization of the mediator influence of CRP in CVD. Our studies will have profound implications on the understanding of CRP function in vascular disease and the full utility of CRP as a biomarker that guides clinical risk assessments and therapeutic strategies to prevent and treat CVD.