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.
Oxidized phospholipids accumulate in atherosclerotic lesions and likely contribute to initiating and sustaining the disease. These studies will determine the mechanism of endothelial cell activation by these lipids to initiate inflammation and thrombosis. In addition they will identify genetic polymorphisms that contribute to endothelial activation for use as prognostic and therapeutic targets.
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