CRP Biology and Vascular Disease

CRP 生物学和血管疾病

• 批准号: 7744625
• 负责人: YUQING Eugene CHEN
• 金额: $ 36.91万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/7744625
• 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; Immigration; 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; Protein C; 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; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Universities; Vascular Diseases; Vascular remodeling; 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; public health relevance; research study; response; response to injury; tool; vascular smooth muscle cell migration; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: C-reactive protein (CRP) is an acute-phase reactant that exhibits increases in plasma levels during infection, systematic inflammation and tissue injury. Recently, epidemiological studies have demonstrated that circulating CRP levels are associated with an increased risk of cardiovascular disease (CVD) among apparently healthy individuals. Although CRP has been shown to have a strong predictive value for future CVD, it is still unclear whether CRP is a non- specific risk marker or a direct mediator in the pathogenesis of CVD. The studies proposed in this application will provide a definitive characterization of the mediator influence of CRP in CVD using CRP transgenic rabbit models. Our studies will have profound implications on the understanding of CRP biology in vascular diseases.

描述（由申请人提供）：尽管C-反应蛋白（CRP）已被证明对未来心血管疾病（CVD）具有很强的预测价值，但目前仍不清楚CRP是CVD发病机制中的非特异性风险标志物还是直接介导物。尽管CRP具有重要的临床意义，但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。在此修订的申请中，我们成功地产生了肝脏特异性（全身）和血管特异性（局部）CRP转基因兔，因为兔具有与人类相似的心血管系统和CRP反应。有趣的是，我们的初步数据首次证明，在肝脏特异性CRP转基因兔中，增加的全身CRP可促进动脉粥样硬化。因此，这两个独特的CRP转基因兔模型的可用性将为我们提供强有力的工具，以确定CRP是否参与CVD的发病机制。在这个建议中，我们将测试的核心假设，肝源性CRP和血管源性CRP的协同作用，以产生最广泛的血管病变的形成，通过激活血管平滑肌细胞增殖和迁移，以应对血管损伤。具体来说，我们将（1）。使用新的转基因兔模型确定CRP参与血管疾病的发病机制，和2）。定义全身CRP与局部CRP作为体内血管病变形成的“血管病变”介质的相对影响。总体而言，这些研究将提供CRP在CVD中的介体影响的明确表征。我们的研究将对理解CRP在血管疾病中的功能以及CRP作为指导临床风险评估和预防和治疗CVD的治疗策略的生物标志物的充分利用产生深远的影响。公共卫生关系：C-反应蛋白（CRP）是一种急性期反应物，在感染、系统性炎症和组织损伤期间表现出血浆水平升高。最近，流行病学研究表明，在表面健康的个体中，循环CRP水平与心血管疾病（CVD）的风险增加相关。尽管CRP已被证明对未来CVD有很强的预测价值，但CRP是CVD发病机制中的非特异性风险标志物还是直接介导物仍不清楚。本申请中提出的研究将使用CRP转基因兔模型提供CRP在CVD中的介质影响的明确表征。我们的研究将对了解CRP在血管疾病中的生物学意义深远。