Molecular Mechanism of Matrix GLA Protein (MGP)

基质 GLA 蛋白 (MGP) 的分子机制

基本信息

批准号：
7576120
负责人：
Kristina I Bostrom
金额：
$ 37.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-24 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7576120
关键词：
Activin Receptor Affect Amino Acids Arterial Fatty Streak Arteries Atherosclerosis BMP2 gene Blood Vessels Bone Growth Bone Matrix Bone Morphogenetic Proteins C-terminal Calcified Cells Cessation of life Clinical Coronary heart disease Data Development Dissection Endothelial Cells Endothelium Feedback Gene Expression Genes Grant Heart Diseases Heart Valves Human Immunoprecipitation Intervention Knockout Mice Laboratories Link Low Density Lipoprotein Receptor Medial Mesenchymal Molecular Morbidity - disease rate Mus Peripheral Process Protein Deficiency Proteins Proteomics Pulmonary artery structure Regulation Reporter Genes Risk Role Rupture Sclerosis Signal Pathway Signal Transduction Smooth Muscle Myocytes Syndrome Testing Transforming Growth Factors Transgenic Mice Tunica Media Vascular Diseases Vascular Endothelial Growth Factors Vascular calcification Vitamin K activin receptor-like kinase 1 artery stenosis bone bone morphogenetic protein 2 bone morphogenetic protein 4 bone morphogenetic protein receptors calcification calcification inhibitor carboxylation coronary artery calcification design improved inhibitor/antagonist insight matrix Gla protein mortality premature prevent protein function protein protein interaction receptor systolic hypertension

项目摘要

Calcification is ubiquitous in vascular disease, and contributes significantly to morbidity and mortality. Matrix GLA protein (MGP) is an alleged calcification inhibitor that is up-regulated in atherosclerotic lesions. Deletion of the MGP gene results in arterial calcification and in morphological abnormalities in mice and humans. MGP is a secreted protein that is modified by vitamin K-dependent g-carboxylation. When isolated from bone, it is processed and lacks seven C-terminal amino acids. The mechanism of MGP is poorly understood. However, our experimental data points to a role in transforming growth factor-fi (TGF-fi) and bone morphogenetic protein (BMP) signaling. The data suggest a potential link between BMP and TGF-li in that BMP2 and BMP-4 induce expression of the TGF-R, receptor Activin-like Kinase receptor 1 (ALK1). Signaling through ALK1 induces MGP, which provides negative feedback regulation for BMP. Interactions between MGP and specific receptors were also observed. Three hypotheses will be tested in this grant. The first hypothesis is that MGP regulates TGF-fi and BMP signaling at the receptor level, resulting in altered SMAD signaling and gene expression. We will characterize activation of SMAD signaling and relevant reporter genes induced by TGF-li1, BMP-2 and BMP-4 in presence of MGP, and identify the TGF-li / BMP receptors that are regulated by MGP. The second hypothesis is that MGP participates in specific protein-protein interactions that may be altered by C-terminal processing. We will characterize the interactions, which include the TGF-ft receptors, using specific immunoprecipitations in combination with a general proteomic approach. The third hypothesis is that MGP functions as a BMP inhibitor in developing arteries and in atherosclerotic lesions. We will generate a transgenic mouse for targeted, conditional expression of the BMP-inhibitor Noggin. Noggin expression will be induced in MGP null mice in attempt to replace MGP and abolish calcification. The effect of Noggin will also be determined in atherosclerotic lesions in LDL-receptor null mice. Our results will add insight to calcification of vessels and heart valves, a common problem in heart disease. In addition, it may provide information on how to design new treatments for unwanted calcification.

钙化在血管疾病中无处不在，并且对发病率和死亡率产生了重大贡献。矩阵 GLA蛋白（MGP）是一种所谓的钙化抑制剂，在动脉粥样硬化病变中被上调。删除 MGP基因导致小鼠和人类的动脉钙化和形态异常。 MGP是一种分泌的蛋白质，通过维生素K依赖性G-羧化而修饰。隔离时骨骼，经过处理，缺乏七个C末端氨基酸。 MGP的机制知之甚少。但是，我们的实验数据指出了转化生长因子-FI（TGF-FI）和骨形态发生蛋白（BMP）信号传导。数据表明 BMP和TGF-LI之间的潜在连接在BMP2和BMP-4诱导TGF-R受体的表达活化素样激酶受体1（ALK1）。通过ALK1发出信号诱导MGP，它提供了负面 BMP的反馈法规。还观察到MGP与特定受体之间的相互作用。这笔赠款将检验三个假设。第一个假设是MGP调节TGF-FI和BMP 在受体水平上的信号传导导致SMAD信号传导和基因表达改变。我们将表征 TGF-LI1，BMP-2和BMP-4在In In In诱导的SMAD信号传导和相关报告基因的激活 MGP的存在，并鉴定由MGP调节的TGF-LI / BMP受体。第二个假设是MGP参与特定的蛋白质 - 蛋白质相互作用，而C末端可能会改变这些相互作用加工。我们将使用特定免疫沉淀与一般蛋白质组学方法结合使用。第三个假设是MGP 在发育中的动脉和动脉粥样硬化病变中充当BMP抑制剂。我们将生成一个转基因小鼠用于靶向的，有条件的BMP抑制剂Noggin的条件表达。 Noggin表达将是在MGP NULL小鼠中诱导以取代MGP并废除钙化。 Noggin的效果也将在LDL受体无效小鼠中的动脉粥样硬化病变中确定。我们的结果将为血管和心脏瓣膜的钙化提供洞察力，这是心脏病中的常见问题。此外，它可能会提供有关如何设计新处理的信息。