MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS

描述(申请人提供)：大量研究从人类和动物模型中检测动脉粥样硬化病变已经确定巨噬细胞在动脉粥样硬化中的中心作用。尽管有这些观察，但目前仍不清楚病变内的变化会导致斑块破裂，而斑块破裂是导致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，在ApoE基因缺失的小鼠原有病变的巨噬细胞中，自激活的基质金属蛋白酶-9的过度表达足以诱导斑块破裂。这项建议将利用这一模型将每两周监测一次的心血管功能变化与病变进展中的细胞和分子变化联系起来。我们还将研究已知的调节巨噬细胞中基质金属蛋白酶-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 在基于巨噬细胞的蛋白质组学分析中确定了新的细胞表面基质金属蛋白酶-9的底物。我们将在体外和体内研究这些新的炎性底物的基质金属蛋白酶-9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.