Role of PAPP-A in Atherosclerosis

PAPP-A 在动脉粥样硬化中的作用

• 批准号: 7637227
• 负责人: Cheryl A. Conover
• 金额: $ 37.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637227
• 关键词: Acute; Arterial Fatty Streak; Atherosclerosis; Attenuated; Binding; Biological Markers; Biology; Blood Vessels; Cause of Death; Cell physiology; Cells; Characteristics; Complex; Coronary; Coronary artery; Development; Diagnosis; Enhancing Lesion; Enzymes; Genes; Growth; Human; Inflammatory Response; Injury; Insulin-Like Growth-Factor-Binding Proteins; Knockout Mice; Lead; Lesion; Mediating; Metalloproteases; Molecular; Mus; Muscle; Myocardial Infarction; PAPP; Play; Pregnancy-Associated Plasma Protein-A; Proteolysis; Receptor Activation; Resistance; Role; Rupture; Serum; Site; Smooth Muscle; Smooth Muscle Myocytes; Societies; Somatomedins; Staining method; Stains; System; Testing; Transgenic Mice; Transgenic Organisms; Zinc; acute coronary syndrome; base; immunoreactivity; macrophage; migration; novel; novel strategies; overexpression; prevent; public health relevance; receptor; response to injury

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.

描述（由申请人提供）：该提案重点关注胰岛素样生长因子（IGF）调节系统中新认识的锌金属蛋白酶，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 通过其对增殖、迁移、存活和分化细胞功能的强大而多样的受体介导作用，在血管损伤反应中发挥着关键作用。 PAPP-A 由血管细胞分泌并与其结合，并且通过局部抑制性 IGF 结合蛋白的蛋白水解裂解，可以增加可用于正在发展的病变内的受体激活的细胞周 IGF。在死于心肌梗塞的人类易损斑块中，已证实与活化的平滑肌细胞和巨噬细胞共定位的强 PAPP-A 免疫反应性，而稳定斑块中很少或没有染色。此外，血清PAPP-A升高被认为是急性冠状动脉综合征肌肉的生物标志物，显示动脉粥样硬化病变加速发展。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脆弱性的关键调节因子。利用新型转基因和条件基因敲除小鼠，本提案的具体目标是： 1. 确定 PAPP-A 增强动脉粥样硬化斑块发展能力所必需的结构决定因素。 2. 确定 PAPP-A 缺乏对已形成的动脉粥样硬化斑块的影响。 3.确定PAPP-A过度表达对斑块脆弱性的影响。拟议的研究旨在更好地了解 PAPP-A 在动脉粥样硬化基础生物学中的作用，并为识别和限制甚至可能逆转动脉粥样硬化斑块生长和脆弱性的新策略奠定科学基础。公共卫生相关性：动脉粥样硬化是西方社会的主要死亡原因。拟议的研究旨在更好地了解与动脉粥样硬化病变发展有关的新发现的酶，并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。