Systems genetics approach to inflammatory mechanisms in atherosclerosis

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PROJECT SUMMARY This proposal is a continuation of work currently funded as a project in a PPG headed by Dr. Alan Fogelman. The PPG must be discontinued because of a limit on the number of cycles allowed, a recent NIH rule. During the last cycle of the grant, we studied 100 diverse strains of mice on a “humanized” hAPOE- Leiden, hCETP background for atherosclerosis traits and for global transcriptomics and metabolomics. We now propose to analyze the data using novel computational approaches, including integration with human data from Genome-Wide Association Studies (GWAS) and expression datasets such as STARNET (Aim 1). We will also continue to make our “systems genetics” data available to all interested investigators, noting that they have now proved useful to many laboratories (Aim 1). Such data generate hypotheses which must be experimentally tested, and we have chosen two genes/pathways based on our long-term interest in inflammation. We will study macrophage colony stimulating factor (M-CSF) as a key regulator of macrophage proliferation (Aim 2). We originally identified M-CSF and other CSFs as the first molecular markers of inflammation in atherosclerosis several decades ago and have continued to study them. Our preliminary data indicate that local M-CSF regulation is key in atherogenesis, and we will test the hypothesis and explore the roles of the three major isoforms. We will also study the transcription factor Zhx2, which we very recently showed to be a key driver of macrophage apoptosis in lesions (Aim 3). Our preliminary data suggest that it interacts with cholesterol loading and other stresses which will be tested. We note that genetic ablation of these two genes has some of the largest effects on lesion size observed. We anticipate that our studies will provide a more comprehensive view of the pathways underlying CVD, a better integration of human and mouse data and an improved understanding of macrophage growth and turnover in lesions. We are hopeful that the studies will lead to new therapeutic or diagnostic advances.