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，磷脂氧化产物（Ox-PAPC）在动脉粥样硬化病变是内皮细胞功能的重要调节因子，影响过度的 mRNA 水平 1000个基因涉及炎症、甾醇调节、凝血、氧化应激、细胞周期、血管生成、氧化还原调节和未折叠的蛋白质反应。对 Ox-PAPC 的炎症反应及其脂质成分 PEIPC 与 IPS 和 TNF 显着不同，导致慢性单核细胞-内皮相互作用的上调。拟议研究的一个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。瞄准 1 我们将使用细胞生物学方法来测试 Ox- 激活的基本信号机制的三个方面 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 改变细胞氧化还原平衡以控制基因表达；并判断是否 PEIPC 与蛋白质的共价结合对于激活非常重要。在目标 2 中，我们将使用综合遗传学方法在转录本水平上定义整个网络，利用共同遗传的概念群体的变化可用于将表达阵列数据组织成生物学相关的模块。我们将利用全基因组关联来绘制网络中常见变异的基因图谱，将数据与正交蛋白质组和功能数据集整合。目标 1 和 2 还包括通过使用 siRNA 以及在某些情况下过度表达来验证重要的调节因子。在目标 3 中，我们将确定三个重要网络调节因子（SREBP、STAT3 和 HO-1）的内皮是否表达在小鼠动脉粥样硬化中起重要作用。对于这些研究，我们将使用 LDL 受体缺失小鼠内皮特异性敲除这些蛋白质。此外，人体病变的炎症区域也会检查这些分子以及我们发现的其他调节网络的分子的表达和激活。这些研究将共同确定控制动脉粥样硬化的潜在内皮靶标。