Regulation of Endothelial Cells by the OX-Papc Network

OX-Papc 网络对内皮细胞的调节

基本信息

批准号：
7647661
负责人：
Judith Anne Berliner
金额：
$ 43.11万
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：
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/7647661
关键词：
Affect Area Arterial Fatty Streak Atherosclerosis Binding Cell Cycle Cell physiology Cells Cellular biology Chronic Coagulation Process Complement Complex Development Disease Endothelial Cells Endothelium Gene Expression Regulation Genes Genetic Genetic Polymorphism Genome Goals Hour Human Immunohistochemistry In Vitro Inflammation Inflammatory Inflammatory Response Knock-out Knockout Mice Lecithin Leprosy Lesion Lipids Lipoproteins Mediating Metabolism Modeling Molecular Mus Oxidative Stress Pathway interactions Phospholipids Play Population Process Proteins Reactive Oxygen Species Receptor Signaling Regulation Research Personnel Rheumatoid Arthritis Role Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Sterols Testing Thrombosis Validation Variant Vascular Endothelial Growth Factor Receptor-2 Woman activating transcription factor angiogenesis base biological adaptation to stress cytokine genome wide association study in vivo inhibitor/antagonist network models oxidized lipid oxidized phosphatidyl choline prognostic receptor response therapeutic target

项目摘要

Our studies have demonstrated that phospholipid oxidation products (Ox-PAPC) which accumulate in atherosclerotic lesions are important regulators of endothelial cell function, affecting mRNA levels of over 1000 genes involving inflammation, sterol regulation, coagulation, oxidative stress, cell cycle, angiogenesis, redox regulation and the unfolded protein response. The inflammatory response to Ox-PAPC and to its component lipid PEIPC was shown to differ significantly from those of IPS and TNF, leading to a chronic upregulation of monocyte-endothelial interactions. A major goal of the proposed studies is to identify the pivotal regulators of the Ox-PAPC/PEIPC network using cell biology and bioinformatics approaches. In Aim 1 we will use a cell biology approach to test three aspects of the basic signaling mechanism activated by Ox- PAPC and PEIPC. We will: define additional components of the Ox-PAPC receptor complex; determine how Ox-PAPC and PEIPC alter the cellular redox balance to contol gene expression; and determine whether covalent binding of PEIPC to proteins is important in activation. In Aim 2, we will use an integrative genetics approach to define the overall network at the transcript level, leveraging the concept that common genetic variations in the population can be used to organize expression array data into biologically relevant modules. We will map the genes contributing to common variation in the network using genome-wide association and integrate the data with orthogonal proteomic and functional datasets. Aims 1 and 2 will also include validation of important regulators by use of siRNA and in some cases overexpression. In Aim 3 we will determine whether endothelial expression of three important network regulators (SREBP, STAT3 and HO-1) plays an important role in atherosclerosis in mice. For these studies, we will employ LDL receptor null mice with endothelial specific knockout of these proteins. In addition, inflammatory areas of human lesions will be examined for expression and activation of these molecules and others we find to regulate the network. Together, these studies will identify potential endothelial targets for the control of atherosclerosis.

我们的研究表明，积累在动脉粥样硬化病变是内皮细胞功能的重要调节剂，影响过度的mRNA水平 1000个涉及炎症，固醇调节，凝结，氧化应激，细胞周期，血管生成的基因氧化还原调节和展开的蛋白质反应。对OX-PAPC及其的炎症反应显示成分脂质PEIPC与IP和TNF的脂质PEIPC显着不同，导致慢性单核细胞 - 内皮相互作用的上调。拟议研究的主要目标是确定使用细胞生物学和生物信息学方法的OX-PAPC/PEIPC网络的关键调节剂。目标 1我们将使用细胞生物学方法来测试由OX-激活的基本信号传导机制的三个方面 PAPC和PEIPC。我们将：定义OX-PAPC受体复合物的其他成分；确定如何 OX-PAPC和PEIPC将细胞氧化还原平衡改变为抑制基因表达。并确定是否 PEIPC与蛋白质的共价结合在激活中很重要。在AIM 2中，我们将使用综合遗传学在转录级别定义整个网络的方法，利用了常见遗传的概念人群的变化可用于将表达阵列数据组织到与生物学相关的模块中。我们将使用全基因组关联和将数据与正交蛋白质组学和功能数据集集成在一起。目标1和2也将包括通过使用siRNA和在某些情况下过表达来验证重要调节剂。在目标3中，我们将确定三个重要网络调节剂的内皮表达（SREBP，STAT3和HO-1）是否在小鼠的动脉粥样硬化中起重要作用。对于这些研究，我们将采用LDL受体无效小鼠这些蛋白质的内皮特异性敲除。此外，人类病变的炎症区域将是检查了这些分子的表达和激活以及我们发现的其他来调节网络的表达和激活。总之，这些研究将确定控制动脉粥样硬化的潜在内皮靶标。