Molecular Mechanism of Matrix GLA Protein (MGP)

基质 GLA 蛋白 (MGP) 的分子机制

• 批准号: 7226328
• 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
• 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/7226328
• 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 Factor beta; Transforming Growth Factor beta Receptors; 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; low density lipoprotein inhibitor; matrix Gla protein; mortality; prevent; protein function; protein protein interaction; receptor; systolic hypertension

DESCRIPTION (provided by applicant): 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-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling. The data suggest a potential link between BMP and TGF-beta in that BMP2 and BMP-4 induce expression of the TGF-beta, 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-beta 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-beta, BMP-2 and BMP-4 in presence of MGP, and identify the TGF-beta / 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-beta receptors, using specific immunoprecipitation 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.

描述（由申请方提供）：钙化在血管疾病中普遍存在，并显著导致发病率和死亡率。基质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上调。MGP基因的缺失导致小鼠和人类的动脉钙化和形态异常。MGP是通过维生素K依赖性g-羧化修饰的分泌蛋白。当从骨中分离时，它被加工并且缺少七个C-末端氨基酸。MGP的机制知之甚少。然而，我们的实验数据指出了转化生长因子-β（TGF-β）和骨形态发生蛋白（BMP）信号传导中的作用。数据表明BMP和TGF-β之间的潜在联系在于BMP 2和BMP-4诱导TGF-β受体激活素样激酶受体1（ALK 1）的表达。通过ALK 1的信号传导诱导MGP，MGP为BMP提供负反馈调节。还观察到MGP与特异性受体之间的相互作用。三个假设将在这次赠款测试。第一个假设是MGP在受体水平调节TGF-β和BMP信号传导，导致SMAD信号传导和基因表达改变。我们将表征在MGP存在下由TGF-β、BMP-2和BMP-4诱导的SMAD信号传导和相关报告基因的激活，并鉴定受MGP调节的TGF-β/ 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，这可能会改变C-末端加工。我们将使用特异性免疫沉淀结合一般蛋白质组学方法来表征包括TGF-β受体在内的相互作用。第三个假设是MGP在动脉发育和动脉粥样硬化病变中起BMP抑制剂的作用。我们将产生一个有针对性的，有条件的表达BMP抑制剂头蛋白的转基因小鼠。将在MGP缺失小鼠中诱导头蛋白表达，以试图替代MGP并消除钙化。还将在LDL受体缺失小鼠的动脉粥样硬化病变中确定头蛋白的作用。我们的研究结果将增加对血管和心脏瓣膜钙化的了解，这是心脏病的常见问题。此外，它还可以提供有关如何为不必要的钙化设计新治疗方法的信息。