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Systems genetics approach to inflammatory mechanisms in atherosclerosis

动脉粥样硬化炎症机制的系统遗传学方法

基本信息

批准号：
10406279
负责人：
Aldons Jake Lusis
金额：
$ 74.29万
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：
2019
资助国家：
美国
起止时间：
2019-07-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406279
关键词：
Ablation Affect Apoptosis Arterial Fatty Streak Atherosclerosis Biological Cardiovascular Diseases Cellular biology Cholesterol Chromosome Mapping Communities Complement Complex Data Data Set Disease Disease Pathway Environment Epigenetic Process Funding Genes Genetic Genetic Databases Genome Goals Grant Growth Heart Human Human Genome Hybrids Inbred Strains Mice Inflammation Inflammatory Inflammatory Response Knock-out Laboratories Lesion Lipids Macrophage Colony-Stimulating Factor Maps Modeling Molecular Genetics Mouse Strains Mus Necrosis Obesity Pathway interactions Plasma Population Production Program Research Project Grants Protein Isoforms Quantitative Trait Loci Regulation Research Personnel Resolution Resources Role Source Stress Structure System Testing Tissues United States National Institutes of Health Variant Work age related atherogenesis base cell type gene expression database genetic analysis genetic approach genetic resource genome wide association study human data improved inflammatory marker insight interest macrophage metabolome metabolomics microbiome molecular marker mouse model network models novel novel diagnostics novel therapeutics population based pressure programs tool trait transcription factor transcriptome transcriptomics

项目摘要

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.

项目总结这项建议是目前作为艾伦博士领导的PPG项目资助的工作的继续福格尔曼。美国国立卫生研究院最近表示，由于允许的周期数量限制，PPG必须停止使用规则。在拨款的最后一个周期中，我们在人性化的hapoe上研究了100个不同品系的小鼠。 HCETP研究动脉粥样硬化特征以及全球转录组学和代谢组学的背景。我们现在建议使用新的计算方法来分析数据，包括与人类数据的集成来自全基因组关联研究(GWAS)和表达数据集，如STARnet(目标1)。我们会还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，指出他们现已证明对许多实验室有用(目标1)。这样的数据产生的假设必须是经过实验测试，我们选择了两个基因/途径，基于我们对发炎。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(目标2)。我们最初确定M-CSF和其他CSF是第一个分子标志物炎症在动脉粥样硬化中的作用早在几十年前就开始了，并且一直在继续研究。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起关键作用，我们将检验这一假说并探索三种主要异构体的作用。我们还将研究转录因子zhx2，我们最近显示是损伤中巨噬细胞凋亡的关键驱动因素(目标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，基因消融这两个基因对病变大小的影响是所观察到的最大的。我们预计，我们的研究将提供CVD潜在途径的更全面的视图，更好地整合人类和小鼠的数据和对病变中巨噬细胞生长和周转的更好的理解。我们满怀希望这些研究将带来新的治疗或诊断进展。