Role of PAPP-A in Atherosclerosis

描述(由申请人提供)：这项提案集中在动脉粥样硬化中胰岛素样生长因子(IGF)调节系统中的一种新发现的金属蛋白酶。IGF在血管损伤反应中发挥重要作用，主要是通过对血管内膜病变中细胞的增殖、迁移、存活和细胞外基质的产生产生强大的影响。血管细胞产生的胰岛素样生长因子结合蛋白(IGFBPs)通过控制IGF与特定细胞表面受体的相互作用来调节局部的IGF生物活性。体外研究表明，抑制IGFBP、IGFBP-4和特定的IGFBP-4酶(IGFBP4-酶)，即所谓的妊娠相关血浆蛋白A(PAPP-A)，参与了细胞对损伤的反应，包括血管损伤。通过以高度调控的方式切割IGFBP-4，IGFBP4-ase/Pappa增加了细胞周围可用于受体激活的IGF。在体内，IGFBP4-ase/PAPP-A在与新生内膜形成平行的受损冠状动脉中被诱导表达。最近，IGFBP4-ASE/PAPP-A在死于心肌梗死的人的罪犯斑块中被证明是免疫反应，其中炎症肩部与平滑肌细胞、巨噬细胞和T淋巴细胞相关的染色最强。我们的总体假设是IGFBP4-ase/PAPP-A在血管损伤反应中是一个关键的IGF调节因子，导致动脉粥样硬化和促进斑块易损性。利用培养的人类细胞和基因工程小鼠，这项提议的具体目标是：1)确定易损斑块中IGFBP4-ase/PAPP-A升高的机制。2)明确IGFBP4-ase/PAPP-A缺陷在动脉粥样硬化斑块发生发展中的作用。3)确定靶向IGFBP4-ase/PAPP-A表达对动脉粥样硬化斑块发生发展的影响。这些研究试图更好地了解动脉粥样硬化的细胞和分子生物学，以便为识别和限制斑块的发展、进展和不稳定性的新策略建立科学基础。

DESCRIPTION (provided by applicant): This proposal focuses on a newly recognized metalloproteinase in the insulin-like growth factor (IGF) regulatory system in atherosclerosis. IGFs play a critical role in the vascular injury response through their potent effects on cell proliferation, migration, survival and extracellular matrix production within the developing intimal lesion. IGF binding proteins (IGFBPs) produced by vascular cells modulate local IGF bioactivity through their control of IGF interaction with specific cell surface receptors. In vitro studies have implicated an inhibitory IGFBP, IGFBP-4, and a specific IGFBP-4 protease (IGFBP4-ase), so-called pregnancy-associated plasma protein A (PAPP-A), in cellular response to injury, including vascular injury. By cleaving IGFBP-4 in a highly regulated manner, IGFBP4-ase/PAPPA increases the pericellular IGF available for receptor activation. In vivo, IGFBP4-ase/PAPP-A expression is induced in injured coronary arteries paralleling the formation of neointima. Recently, IGFBP4-ase/PAPP-A immunoreactivity was demonstrated in culprit plaques of humans who had died of myocardial infarction, with the most intense staining in the inflammatory shoulder associated with smooth muscle cells, macrophages, and T-lymphocytes. Our overall hypothesis is that IGFBP4- ase/PAPP-A is a key IGF regulatory factor in the vascular response to injury leading to atherosclerosis and promoting plaque vulnerability. Utilizing cultured human cells and genetically engineered mice, the SPECIFIC AIMS of this proposal are to: 1) Determine the mechanisms underlying elevated IGFBP4-ase/PAPP-A in vulnerable plaque. 2) Determine the effect of IGFBP4-ase/PAPP-A deficiency on the development and progression of atherosclerotic plaque. 3) Determine the effect of targeted IGFBP4-ase/PAPP-A expression on the development and progression of atherosclerotic plaque. These studies seek to gain a better understanding of the cellular and molecular biology of atherosclerosis in order to establish a scientific basis for novel strategies to identify and limit plaque development, progression, and instability.