CRP Biology and Vascular Disease

摘要 尽管C反应蛋白（CRP）已被证明对以下疾病具有很强的预测价值： 未来心血管疾病（CVD），目前尚不清楚CRP是否是一种非特异性风险 标志物或直接介导的CVD的发病机制。尽管它在临床上很重要 目前缺乏合适的动物模型来研究其在CVD中的作用，因为小鼠 不是研究CRP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，因为兔子有心血管系统和CRP反应， 与人类相似。有趣的是，我们的初步数据首次记录了 增加的全身CRP可以促进肝特异性CRP转基因小鼠的动脉粥样硬化， 家兔因此，这两种独特的CRP转基因兔模型的可用性将提供 我们的有力工具，以确定是否CRP参与CVD的发病机制。在这一提议中， 我们将检验肝源性CRP和血管源性CRP均起作用的中心假设， 协同地通过激活血管，产生最广泛的血管损伤形成， 平滑肌细胞增殖和迁移对血管损伤的反应。我们特别 将1）。使用新的方法确定CRP参与血管疾病的发病机制 转基因兔模型，和2）。定义全身CRP与局部CRP的相对影响 CRP作为体内血管病变形成的“血管病性”介质。 总的来说，这些研究将提供一个明确的表征调解人的影响 CRP在CVD中我们的研究将对CRP的理解产生深远的影响 在血管疾病中的作用以及CRP作为指导临床风险的生物标志物的充分利用 评估和治疗策略，以预防和治疗CVD。

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.