Role of PAPP-A in Atherosclerosis

描述(申请人提供)：这项提案集中在胰岛素样生长因子(IGF)调节系统中的一种新发现的锌金属蛋白酶，即所谓的妊娠相关血浆蛋白-A(PAPP-A)，及其在动脉粥样硬化中的作用。IGF通过其强大而多样的受体介导的增殖、迁移、存活和分化细胞功能在血管损伤反应中发挥关键作用。PAPP-A由血管细胞分泌并结合到血管细胞上，通过对局部抑制性IGF结合蛋白的蛋白水解性切割，可以增加细胞周围可用于发展中病变内受体激活的IGF。在死于心肌梗死的人的易损斑块中，PAPP-A与激活的平滑肌细胞和巨噬细胞共定位，而在稳定的斑块中几乎没有染色。此外，血清PAPP-A升高被认为是急性冠脉综合征肌肉显示动脉粥样硬化病变加速发展的生物标志物。我们的总体假设是，PAPP-A是促进动脉粥样硬化斑块发展和斑块易损性的关键调节因子。利用新的转基因和条件性基因敲除小鼠，本方案的具体目的是：1.确定PAPP-A促进动脉粥样硬化斑块发展所必需的结构决定因素。2.确定PAPP-A缺乏对已建立的动脉粥样硬化斑块的影响。3.确定PAPP-A过表达对斑块易损性的影响。拟议的研究试图在动脉粥样硬化的基础生物学中更好地了解PAPP-A，并应为识别和限制、并可能逆转动脉粥样硬化斑块生长和易损性的新策略建立科学基础。公共卫生相关性：动脉粥样硬化是西方化社会的主要死亡原因。拟议的研究试图更好地了解一种新发现的与动脉粥样硬化病变发展有关的酶，并应为识别和限制(甚至可能逆转)动脉粥样硬化的新策略奠定科学基础。

DESCRIPTION (provided by applicant): This proposal focuses on a newly recognized zinc metalloproteinase in the insulin-like growth factor (IGF) regulatory system, so-called pregnancy-associated plasma protein-A (PAPP-A), and its role in atherosclerosis. IGFs play a critical role in the vascular injury response through their potent and varied receptor-mediated effects on proliferation, migration, survival and differentiated cell function. PAPP-A is secreted by and binds to vascular cells, and, by proteolytic cleavage of local inhibitory IGF binding proteins, can increase the pericellular IGF available for receptor activation within the developing lesion. Strong PAPP-A immunoreactivity co-localizing with activated smooth muscle cells and macrophages has been demonstrated in vulnerable plaques of humans who had died of myocardial infarction with little or no staining in stable plaques. In addition, elevated serum PAPP-A is under consideration as a biomarker of acute coronary syndro muscle show accelerated atherosclerotic lesion development. Our overall hypothesis is that PAPP-A is a key regulatory factor promoting atherosclerotic plaque development and plaque vulnerability. Utilizing novel transgenic and conditional gene knock-out mice, the SPECIFIC AIMS of this proposal are to: 1. Ascertain the structural determinants of PAPP-A necessary for its ability to enhance atherosclerotic plaque development. 2. Determine the effect of PAPP-A deficiency on established atherosclerotic plaque. 3. Determine the effect of PAPP-A overexpression on plaque vulnerability. The proposed studies seek to gain a better understanding of PAPP-A in the fundamental biology of atherosclerosis, and should establish a scientific basis for novel strategies to identify and limit, and possibly reverse, plaque growth and vulnerability in atherosclerosis. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the major cause of death in westernized societies. The proposed studies seek to gain a better understanding of a newly discovered enzyme implicated in atherosclerotic lesion development and should establish a scientific basis for novel strategies to identify and limit, and possibly reverse, atherosclerosis.