Molecular Mechanisms of Vascular Calcification

血管钙化的分子机制

• 批准号: 7647663
• 负责人: Kristina I Bostrom
• 金额: $ 36.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647663
• 关键词: ACVR1 gene; ATP-Binding Cassette Transporters; Address; Affect; Alkaline Phosphatase; Animals; Ankylosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Back; Binding; Blood Vessels; Bone Morphogenetic Proteins; Breeding; Calcified; Calcium; Cardiovascular system; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Complement; Complement Factor B; Complex; Critiques; Data; Development; Disease; Dose; Dystrophic Calcification; Elastic Fiber; Feedback; Figs - dietary; Gene Targeting; Genes; Genetic; Grant; Heart Diseases; Hepatic; Hereditary hemorrhagic telangiectasia; Human; In Vitro; Inflammation Mediators; Inflammatory; Kidney; Knockout Mice; Knowledge; Lesion; Ligands; Link; Lipids; Lipoproteins; Liver; Medial; Mediating; Mediator of activation protein; Mesenchymal; Metabolism; Minerals; Modeling; Molecular; Mus; Muscle Cells; Mutate; Mutation; Myocardial; Nature; Organ; Pathway interactions; Poorly Differentiated Lesion; Precipitation; Prevention; Principal Investigator; Proline; Protein Binding; Pseudoxanthoma Elasticum; Published Comment; Quantitative Trait Loci; Receptor Signaling; Regulatory Pathway; Reporting; Research Personnel; Role; Severities; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Testing; Transforming Growth Factors; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular calcification; Work; activin receptor-like kinase 1; atherogenesis; base; bone morphogenetic protein 2; bone morphogenetic protein 4; bone morphogenetic protein 9; bone morphogenetic protein receptor type II; bone morphogenetic protein receptors; calcification; cell type; chelation; data modeling; design; extracellular; feeding; in vivo; inhibitor/antagonist; matrix Gla protein; mineralization; mouse model; osteogenic; osteopontin; overexpression; phosphoric diester hydrolase; prevent; programs; protective effect; pyrophosphatase; receptor; receptor expression; research study; segregation; therapy development

Prevention of vascular calcification is mediated in part by Matrix Gla Protein (MGP) and the hepatic ABC transporter C6 (AbccG). MGP is a secreted matrix protein and may affect vascular calcification in vivo by binding bone morphogenetic proteins (BMP) and/or calcium through gamma-carboxylated glutamates. Our data show that in vascular cells BMP-2/4 induce expression of the activin-like kinase receptor 1 (ALK1), an essential TGF-3 receptor in vascular development. ALK1 is also expressed in atherosclerotic lesions and promotes aggregation and proliferation of cultured lesion cells. Induction of the ALK1 receptor allows BMP- 2/4 to regulate expression of vascular endothelial growth factor and MGP, which provides a feed back loop to limit BMP-activity. The importance of this pathway in atherogenesis is unknown. Abcc6 is a membrane transporter that is mainly expressed in the liver. AbccG was identified in our previous studies using an integrative genomics approach, and was shown to protect against vascular calcification. Abcc6 deficiency has been associated with pseudoxanthoma elasticum that is characterized by progressive calcification and accelerated atherosclerosis. The site and the mechanism of action of Abcc6 are not understood. This application focuses on the mechanisms by which MGP and Abcc6 prevent vascular calcification, and the effect of ALK1 and Abcc6 on atherogenesis. Four specific aims will be addressed. In Specific Aim 1; we will determine the importance of BMP-binding versus calcium-binding for the ability of MGP to inhibit vascular calcification in vivo using homologous recombination in mice. In Specific Aim 2, we will identify the receptor(s) and signaling pathway(s) that are required for BMP-2/4 to induce expression of the ALK1- receptor using siRNA, dominant negative receptors and molecular inhibitors in vitro. Specific Aim 3 will address Abcc6 and Abcc6 related pathways and determine the site and the molecular basis of its inhibitory effect on vascular calcification using both in vitro and in vivo techniques. Finally, in Specific Aim 4, we will address the effects of modulating expression of ALK1 and Abcc6 on lesion development in established mouse models of atherosclerosis.

基质GLA蛋白(MGP)和肝ABC部分介导血管钙化的预防 转运蛋白C6(AbccG)。MGP是一种分泌型基质蛋白，可能通过以下途径影响体内血管钙化 通过伽玛-羧化谷氨酸结合骨形态发生蛋白(BMP)和/或钙。我们的 研究表明，在血管细胞中，BMP-2/4诱导激活素样激酶受体1(ALK1)的表达。 血管发育中必需的转化生长因子-3受体ALK1在动脉粥样硬化病变中也有表达， 促进培养的病变细胞的聚集和增殖。ALK1受体的诱导使BMP- 2/4调节血管内皮生长因子和MGP的表达，提供反馈环 以限制BMP的活性。这一途径在动脉粥样硬化形成中的重要性尚不清楚。Abcc6是一种膜 主要在肝脏表达的转运蛋白。在我们之前的研究中，我们使用一种 综合基因组学方法，并被证明对血管钙化具有保护作用。Abcc6缺乏症 与弹性假黄瘤有关，其特征是进行性钙化和 加速动脉粥样硬化。Abcc6的作用部位和作用机制尚不清楚。这 应用重点是MGP和Abcc6防止血管钙化的机制，以及MGP和Abcc6 ALK1和Abcc6在动脉粥样硬化形成中的作用。将解决四个具体目标。具体目标1；我们将 确定BMP结合与钙结合对MGP抑制血管的能力的重要性 在小鼠体内利用同源重组进行钙化。在具体目标2中，我们将确定 骨形态发生蛋白-2/4诱导碱性磷酸酶1表达所需的受体(S)和信号通路(S) 受体使用siRNA，显性负性受体和分子抑制物在体外。具体目标3将 定位Abcc6和Abcc6相关通路，确定其抑制作用的部位和分子基础 使用体外和体内技术对血管钙化的影响。最后，在具体目标4中，我们将 调控ALK1和Abcc6的表达对已建立的大鼠皮损发展的影响 动脉粥样硬化的小鼠模型。