Lipid phosphate phosphatase 3 as a novel atherosclerosis suppressor

脂质磷酸磷酸酶 3 作为新型动脉粥样硬化抑制剂

基本信息

批准号：
8888525
负责人：
ANDREW J MORRIS
金额：
$ 52.11万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888525
关键词：
Acute myocardial infarction Alleles Arterial Fatty Streak Atherosclerosis Attenuated Binding Biological Availability Blood Cells Blood Vessels CCAAT-Enhancer-Binding Proteins Cardiovascular Diseases Cardiovascular system Cause of Death Cell Proliferation Cell Survival Cell surface Cells Clinical Complement Coronary Arteriosclerosis Coronary artery Cultured Cells Data Analyses Deposition Development Developmental Process Diagnosis Disease Drosophila genus Employee Strikes Enhancers Enzymes Event Experimental Models Family Gene Expression Genes Genetic Genetic Polymorphism Genetic Transcription Genetic Variation Goals Homologous Gene Human Human Genetics Hyperplasia Inflammatory Injury Introns Investigation Knowledge Lipids Lysophospholipids Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Molecular Mus Myocardial Infarction Myocardial Ischemia Phospholipids Phosphoric Monoester Hydrolases Physiological Processes Positioning Attribute Predisposition Publishing Reagent Recording of previous events Research Research Project Grants Resolution Risk Risk Factors Role Series Signal Transduction Single Nucleotide Polymorphism Site Site-Directed Mutagenesis Smooth Muscle Myocytes Stable Isotope Labeling Stimulus Testing Therapeutic Tissues United States Up-Regulation Variant Work base cardiovascular disorder risk cell motility disorder risk extracellular genetic variant genome wide association study improved innovation inorganic phosphate insight lipid mediator lipid metabolism lipid phosphate phosphatase lysophosphatidic acid macrophage monocyte mortality mouse model novel novel therapeutics oxidized low density lipoprotein prevent public health relevance response risk variant tool vascular inflammation

Acute myocardial infarction Alleles Arterial Fatty Streak Atherosclerosis Attenuated Binding Biological Availability Blood Cells Blood Vessels CCAAT-Enhancer-Binding Proteins Cardiovascular Diseases Cardiovascular system Cause of Death Cell Proliferation Cell Survival Cell surface Cells Clinical Complement Coronary Arteriosclerosis Coronary artery Cultured Cells Data Analyses Deposition Development Developmental Process Diagnosis Disease Drosophila genus Employee Strikes Enhancers Enzymes Event Experimental Models Family Gene Expression Genes Genetic Genetic Polymorphism Genetic Transcription Genetic Variation Goals Homologous Gene Human Human Genetics Hyperplasia Inflammatory Injury Introns Investigation Knowledge Lipids Lysophospholipids Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Molecular Mus Myocardial Infarction Myocardial Ischemia Phospholipids Phosphoric Monoester Hydrolases Physiological Processes Positioning Attribute Predisposition Publishing Reagent Recording of previous events Research Research Project Grants Resolution Risk Risk Factors Role Series Signal Transduction Single Nucleotide Polymorphism Site Site-Directed Mutagenesis Smooth Muscle Myocytes Stable Isotope Labeling Stimulus Testing Therapeutic Tissues United States Up-Regulation Variant Work base cardiovascular disorder risk cell motility disorder risk extracellular genetic variant genome wide association study improved innovation inorganic phosphate insight lipid mediator lipid metabolism lipid phosphate phosphatase lysophosphatidic acid macrophage monocyte mortality mouse model novel novel therapeutics oxidized low density lipoprotein prevent public health relevance response risk variant tool vascular inflammation

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项目摘要

DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA) is an essential bioactive phospholipid mediator that regulates a range of developmental and physiological processes which are emerging as targets for a new class of molecular therapeutics. In the cardiovascular system, LPA is poised to serve as a mediator of atherothrombotic disease: it is abundant in atherosclerotic plaque, increases during acute myocardial infarction, triggers phenotypic responses in smooth muscle cells, and disrupts endothelial integrity. We and others have demonstrated that LPA promotes both the development of intimal hyperplasia following injury and atherosclerosis in experimental models. Lipid phosphate phosphatase 3 (LPP3), encoded by the PPAP2B gene, is an integral membrane enzyme that regulates the bioavailability of LPA. We have recently demonstrated that LPP3 is an intrinsic negative regulator of vascular inflammation, suppresses smooth muscle cell proliferation, and promotes endothelial barrier function likely by limiting LPA signaling. Analysis of data from a series of genome-wide association studies of coronary artery disease (CAD) identified a striking association between the PPAP2B locus and myocardial infarction. We provide evidence that CAD-risk associated PPAP2B variant disrupts an intronic enhancer that increases transcription of the gene and LPP3 expression in ox-LDL stimulated macrophages. These findings suggest the testable hypothesis that LPP3 functions as an atherosclerosis suppressor and that reduced PPAP2B gene expression aggravates cellular events underlying atherosclerosis and increases the likelihood of myocardial infarction. In this proposal, we will define the role of LPP3 in the development of atherosclerosis, provide insight into the molecular mechanism(s) involved, and validate the predicted risk allele associated with CAD in humans. We are uniquely well-prepared to achieve these goals based on our expertise in bioactive lipid signaling and the tools we have amassed to study LPP3. Completion of these studies promises to provide valuable insight into the mechanism(s) by which extracellular bioactive lipid mediators influence the development of atherosclerosis and provide novel and innovative targets to predict, prevent and treat CAD.

描述（由适用提供）：溶物磷脂酸（LPA）是一种必不可少的生物活性磷脂介质，可调节一系列发育和物理过程，这些过程正在成为新的分子疗法的靶标。在心血管系统中，LPA被中毒成为动脉粥样硬化疾病的介体：它在动脉粥样硬化斑块中很丰富，在急性心肌梗死过程中增加，在平滑肌细胞中触发表型反应，并破坏内皮整合性。我们和其他人已经证明，LPA在损伤后促进了内膜增生的发展和实验模型中的动脉粥样硬化。由PPAP2B基因编码的脂质磷酸磷酸盐磷酸酶3（LPP3）是一种积分膜酶，可调节LPA的生物利用度。我们最近证明，LPP3是血管感染的固有负调节剂，抑制平滑肌细胞增殖，并通过限制LPA信号传导来促进内皮屏障功能。分析来自冠状动脉疾病（CAD）一系列全基因组关联研究的数据，确定了PPAP2B基因座和心肌梗塞之间的罢工关联。我们提供的证据表明，CAD风险相关的PPAP2B变体破坏了内含子增强子，该增强子增加了OX-LDL刺激的巨噬细胞中基因和LPP3表达的转录。这些发现表明，LPP3作为动脉粥样硬化抑制剂的可检验假设，并且降低了PPAP2B基因表达会加剧动脉粥样硬化潜在的细胞事件并增加心肌梗死的可能性。在此提案中，我们将定义LPP3在动脉粥样硬化发展中的作用，提供对所涉及的分子机制的见解，并验证与人类中CAD相关的预测风险等位基因。根据我们在生物活性脂质信号传导方面的专业知识以及我们积累了研究LPP3的工具，我们为实现这些目标做好了充分的准备。这些研究的完成有望为细胞外生物活性脂质介体影响动脉粥样硬化的发展并提供新颖而创新的目标以预测，预防和治疗CAD的新型机制提供宝贵的见解。