Complement, Cardiovascular Disease, and SLE

补体、心血管疾病和系统性红斑狼疮

基本信息

  • 批准号:
    6733758
  • 负责人:
  • 金额:
    $ 34.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-09-30 至 2007-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Inflammation is now recognized as a critical process in the development and rupture of atherosclerotic plaques, and in the morbidity and mortality that result from cardiovascular disease. Recent studies have also suggested that this process may be accelerated and exaggerated in patients with systemic lupus erythematosus. We have recently established a research program focused on vascular biology and pathology, with a focus on lupus as a model of accelerated atherosclerosis. The stimulus for these investigations was a recent surprising observation by Manzi and colleagues who demonstrated a strong linear association between elevated serum levels of C3 and C4 and aortic stiffness in premenopausal women with SLE. Whereas decreased serum levels of C3 and C4 have traditionally been used to monitor disease activity in patients with SLE, association of elevated serum levels of serum complement components with any disease process is unprecedented. This observation led us to investigate the potential role(s) for complement C3 and C4 in the immunopathogenesis of cardiovascular disease in SLE. Vascular imaging studies led to several intriguing and unexpected observations that will be further explored here. First, we discovered that complement components C3 and C4 are present in several distinct patterns within the arterial walls of both humans and mice. Specifically, proteolytic fragments of C3 and C4 co-localize with, and may be covalently bound to, elastin within the arterial wall. This entirely unexpected observation suggested that complement deposition within the arterial wall may increase vascular stiffness, an early event in atherosclerosis, through direct interference with elastic fiber flexibility. Second, we observed aggregates of complement deposition within the vessel wall, the site at which plaque formation is now known to initiate. Third, we demonstrated that complement components are specifically present within the vasculature of mice with lupus-like syndromes as compared with controls. These observations, together with those of Manzi and colleagues, have led to the following specific aims that are based on our central hypothesis that the complement system may influence vascular stiffness and contribute significantly to the atherosclerotic process by directly reducing vascular elasticity within the arterial wall. The long-term goal of this proposal is to perform an initial characterization of the role of the complement system in atherosclerosis, using normal and abnormal human and mouse vascular systems. Specific Aim 1 is to characterize the spatial and temporal localization of complement proteins C3 and C4 within the arterial wall. Specific Aim 2 is to characterize the distribution of complement C3 and C4 within the arterial tree. Specific Aim 3 is to determine the capacity of complement C3 and C4 within the arterial wall to increase arterial stiffness. These studies will represent the first rigorous investigation of the role of the complement system in atherosclerosis, using SLE as a model of accelerated coronary vascular disease. Ultimately, the data generated by the proposed studies should identify therapeutic targets in SLE and in atherosclerosis in general.
描述(由申请人提供): 炎症是动脉粥样硬化斑块形成和破裂的关键过程,也是导致心血管疾病发病率和死亡率的重要因素。最近的研究还表明,这一过程可能会加速和夸大系统性红斑狼疮患者。我们最近建立了一个研究项目,重点是血管生物学和病理学,重点是狼疮作为加速动脉粥样硬化的模型。这些研究的刺激因素是Manzi及其同事最近的一项令人惊讶的观察结果,他们证明了绝经前SLE女性血清C3和C4水平升高与主动脉僵硬度之间存在强烈的线性相关性。尽管C3和C4的血清水平降低传统上用于监测SLE患者的疾病活动,但血清补体成分的血清水平升高与任何疾病过程的关联是前所未有的。这一观察使我们研究补体C3和C4在SLE心血管疾病免疫发病机制中的潜在作用。血管成像研究导致了几个有趣的和意想不到的观察,将在这里进一步探讨。首先,我们发现补体成分C3和C4以几种不同的模式存在于人和小鼠的动脉壁内。具体地,C3和C4的蛋白水解片段与动脉壁内的弹性蛋白共定位,并且可以共价结合至动脉壁内的弹性蛋白。这一完全出乎意料的观察结果表明,动脉壁内的补体沉积可能通过直接干扰弹性纤维的柔韧性而增加血管硬度,这是动脉粥样硬化的早期事件。第二,我们观察到补体聚集沉积在血管壁内,现在已知斑块形成的起始部位。第三,我们证明了与对照组相比,狼疮样综合征小鼠的血管系统中特异性存在补体成分。这些观察结果与Manzi及其同事的观察结果一起,导致了以下具体目标,这些目标基于我们的中心假设,即补体系统可能影响血管硬度,并通过直接降低动脉壁内的血管弹性而显著促进动脉粥样硬化过程。本提案的长期目标是使用正常和异常的人和小鼠血管系统对补体系统在动脉粥样硬化中的作用进行初步表征。具体目标1是表征补体蛋白C3和C4在动脉壁内的空间和时间定位。具体目标2是表征补体C3和C4在动脉树内的分布。具体目标3是确定动脉壁内补体C3和C4增加动脉僵硬度的能力。这些研究将代表补体系统在动脉粥样硬化中的作用的第一次严格的调查,使用SLE作为加速冠状动脉血管疾病的模型。最终,拟议的研究产生的数据应该确定SLE和动脉粥样硬化的治疗靶点。

项目成果

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Joseph M Ahearn其他文献

Joseph M Ahearn的其他文献

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{{ truncateString('Joseph M Ahearn', 18)}}的其他基金

Complement, Cardiovascular Disease, and SLE
补体、心血管疾病和系统性红斑狼疮
  • 批准号:
    6805641
  • 财政年份:
    2003
  • 资助金额:
    $ 34.99万
  • 项目类别:
Erythrocytes as Time Capsules of Disease Activity in SLE
红细胞作为系统性红斑狼疮疾病活动的时间胶囊
  • 批准号:
    6772602
  • 财政年份:
    2003
  • 资助金额:
    $ 34.99万
  • 项目类别:
Erythrocytes as Time Capsules of Disease Activity in SLE
红细胞作为系统性红斑狼疮疾病活动的时间胶囊
  • 批准号:
    7105057
  • 财政年份:
    2003
  • 资助金额:
    $ 34.99万
  • 项目类别:
Erythrocytes as Time Capsules of Disease Activity in SLE
红细胞作为系统性红斑狼疮疾病活动的时间胶囊
  • 批准号:
    6924619
  • 财政年份:
    2003
  • 资助金额:
    $ 34.99万
  • 项目类别:
Complement, Cardiovascular Disease, and SLE
补体、心血管疾病和系统性红斑狼疮
  • 批准号:
    6898927
  • 财政年份:
    2003
  • 资助金额:
    $ 34.99万
  • 项目类别:
Complement, Cardiovascular Disease, and SLE
补体、心血管疾病和系统性红斑狼疮
  • 批准号:
    7077805
  • 财政年份:
    2003
  • 资助金额:
    $ 34.99万
  • 项目类别:
Erythrocytes as Time Capsules of Disease Activity in Systemic Lupus Erythematosus
红细胞作为系统性红斑狼疮疾病活动的时间胶囊
  • 批准号:
    7253944
  • 财政年份:
    2003
  • 资助金额:
    $ 34.99万
  • 项目类别:
Erythrocytes as Time Capsules of Disease Activity in SLE
红细胞作为系统性红斑狼疮疾病活动的时间胶囊
  • 批准号:
    6677400
  • 财政年份:
    2003
  • 资助金额:
    $ 34.99万
  • 项目类别:
DAMAGE AND PATHOLOGIC FRACTURE IN VERTEBRAL BODIES
椎体损伤和病理性骨折
  • 批准号:
    6232932
  • 财政年份:
    2001
  • 资助金额:
    $ 34.99万
  • 项目类别:
Rheumatic Diseases Core Center
风湿病核心中心
  • 批准号:
    6632786
  • 财政年份:
    2001
  • 资助金额:
    $ 34.99万
  • 项目类别:

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