MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS

描述（由申请人提供）：许多研究检查了来自人类和动物模型的动脉粥样硬化病变，已经确定了巨噬细胞在动脉粥样硬化中的中心作用。尽管有这些观察结果，但仍不清楚病变内的什么变化导致斑块破裂，斑块破裂是动脉粥样硬化的大多数临床表现的原因。我们最近首次表明，ApoE缺失小鼠预先存在的病变的巨噬细胞中自活化MMP-9的过表达足以诱导斑块破裂。该提案将利用该模型将每2周监测的心血管功能变化与病变进展中的细胞和分子变化相关联。我们还将研究已知调节巨噬细胞MMP-9活性的不同因素的作用，包括与疾病进展有关的氧化应激。最后我们 已经在基于巨噬细胞的蛋白质组学分析中鉴定了MMP-9的新型细胞表面底物。我们将在体外和体内表征MMP-9裂解这些新的炎症底物的性质和生物学意义。

DESCRIPTION (provided by applicant): Numerous studies examining atherosclerotic lesions from human and animal models have established the central role of the macrophage in atherosclerosis. Despite these observations, it is still unclear what changes within the lesions result in plaque rupture that is responsible for the majority of clinical manifestations of atherosclerosis, We have recently shown for the first time that overexpression of auto-activated MMP-9 in macrophages of pre-existing lesions of ApoE null mice is sufficient to induce plaque rupture. This proposal will utilize this model to correlate changes in cardiovascular function monitored every 2 weeks with cellular and molecular changes in lesion progression. We will also examine the role of different factors known to regulate MMP-9 activity in macrophages, including oxidative stress that has been linked to disease progression. Finally, we have identified novel cell surface substrates of MMP-9 in a macrophage-based proteomics analysis. We will characterize the nature and biological significance of MMP-9 cleavage of these novel inflammatory substrates in vitro and in vivo.