Systems genetics approach to inflammatory mechanisms in atherosclerosis

项目摘要 该提案是目前作为由Alan博士领导的PPG项目资助的工作的延续。 福格曼。PPG必须停止，因为允许的周期数有限，最近NIH 统治在最后一个周期的赠款，我们研究了100个不同品系的小鼠对“人源化”的hAPOE- Leiden，hCETP背景，用于动脉粥样硬化特征和全局转录组学和代谢组学。我们 现在，我建议使用新的计算方法来分析数据，包括与人类数据的整合 来自全基因组关联研究（GWAS）和表达数据集，如STARNET（Aim 1）。我们将 我们也继续向所有感兴趣的研究人员提供我们的“系统遗传学”数据，并指出， 现在已经证明对许多实验室有用（目标1）。这些数据产生的假设必须是 实验测试，我们已经选择了两个基因/途径，基于我们的长期利益， 炎症我们将研究巨噬细胞集落刺激因子（M-CSF）作为巨噬细胞的关键调节因子， 增殖（目的2）。我们最初将M-CSF和其他CSF确定为第一个分子标记物， 在动脉粥样硬化炎症几十年前，并继续研究他们。我们的初步数据 表明局部M-CSF调节在动脉粥样硬化形成中是关键，我们将检验这一假设并探索 三种主要异构体的作用。我们还将研究转录因子Zhx 2，我们最近 显示是病变中巨噬细胞凋亡的关键驱动因素（目的3）。我们的初步数据显示 与胆固醇负荷和其他将被测试的压力相互作用。我们注意到， 这两个基因对观察到的损伤大小具有最大的影响。我们预计，我们的研究将 提供了一个更全面的看法的途径，潜在的心血管疾病，更好地整合人类和 小鼠数据，以及对损伤中巨噬细胞生长和周转的更好理解。我们希望 这些研究将带来新的治疗或诊断进展。

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.