CRP Biology and Vascular Disease

CRP 生物学和血管疾病

基本信息

批准号：
8197874
负责人：
YUQING Eugene CHEN
金额：
$ 36.44万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-10 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197874
关键词：
Acute-Phase Proteins Acute-Phase Reaction Address Animal Model Apolipoprotein E Area Arterial Fatty Streak Atherosclerosis Biological Markers Biological Models Biology Blood Circulation Blood Vessels Breeding C-reactive protein CCL2 gene Cardiovascular Diseases Cardiovascular system Cell physiology Cholesterol Clinical Collaborations Data Development Diet Engineering Epidemiologic Studies Event Exhibits Future Gene Expression Profile Generations Human IL8 gene Individual Infection Inflammation Inflammatory Injury Lesion Liver Mediator of activation protein Modeling Molecular Mus Myosin Heavy Chains Oryctolagus cuniculus Participant Pathogenesis Pathway interactions Plasma Predictive Value Regulation Relative (related person)Research Personnel Risk Risk Assessment Risk Marker Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Smooth Muscle Myosins Source Structure System TNF gene Testing Therapeutic Time Tissues Transgenic Mice Transgenic Organisms Universities Vascular Diseases Vascular remodeling abstracting atherogenesis autocrine cardiovascular disorder risk cardiovascular injury cell motility cerebrovascular in vitro Model in vivo insight interest migration mouse model novel overexpression paracrine prevent promoter protein expression protein function research study response response to injury tool vascular smooth muscle cell migration vascular smooth muscle cell proliferation

项目摘要

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.

摘要尽管已证明C反应蛋白（CRP）具有强的预测值未来的心血管疾病（CVD），尚不清楚CRP是否是非特异性风险 CVD发病机理中的标记或直接介体。尽管临床非常重要在CRP中，我们目前缺乏适当的动物模型来研究其在CVD中的作用，因为小鼠是不是研究CRP功能的合适动物模型。在此修订的应用程序中，我们有成功产生了肝特异性（全身）和血管特异性（本地）CRP 转基因兔子，因为兔子具有心血管系统和CRP反应与人类类似。有趣的是，我们的初步数据首次记录了增加的全身性CRP可以促进肝特异性CRP转基因的动脉粥样硬化兔子。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定义CRP是否参与CVD的发病机理。在此提案中，我们将测试肝脏衍生的CRP和血管衍生的CRP ACT的中心假设通过激活血管来协同产生最广泛的血管病变形成平滑肌细胞的增殖和响应血管损伤的迁移。具体来说，我们会1）。定义CRP使用新型参与血管疾病的发病机理转基因兔模型，2）。定义系统性CRP与本地的相对影响 CRP是体内血管病变形成的“血管性”介体。总体而言，这些研究将为调解人的影响提供明确的特征 CVD中的CRP。我们的研究将对对CRP的理解产生深远的影响血管疾病的功能和CRP作为指导临床风险的生物标志物的全部功能预防和治疗CVD的评估和治疗策略。