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

• 批准号: 9797558
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-12 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9797558
• 关键词: Ablation; Affect; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Biological; Cardiovascular Diseases; Cellular biology; Cholesterol; Chromosome Mapping; Communities; Complement; Complex; Data; Data Set; Databases; Disease; Disease Pathway; Environment; Epigenetic Process; Funding; Gene Expression; 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; 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

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.

项目概要 该提案是目前由 Alan 博士领导的 PPG 项目资助的工作的延续 福格曼. NIH 最近的一项研究表明，由于允许的周期数受到限制，PPG 必须停止 规则。在资助的最后一个周期中，我们在“人源化”hAPOE 上研究了 100 种不同品系的小鼠 Leiden，hCETP 动脉粥样硬化特征以及全球转录组学和代谢组学背景。我们 现在建议使用新颖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 STARNET 等表达数据集（目标 1）。我们将 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，并指出他们 现已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 经过实验测试，我们根据我们的长期兴趣选择了两个基因/途径 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 扩散（目标 2）。我们最初将 M-CSF 和其他 CSF 确定为第一个分子标记 几十年前，人们对动脉粥样硬化中的炎症进行了研究，并继续对其进行研究。我们的初步数据 表明局部 M-CSF 调节是动脉粥样硬化形成的关键，我们将检验该假设并探索 三种主要亚型的作用。我们还将研究转录因子 Zhx2，我们最近 已被证明是病变中巨噬细胞凋亡的关键驱动因素（目标 3）。我们的初步数据表明 与胆固醇负荷和其他将要测试的压力相互作用。我们注意到基因消融 这两个基因对观察到的病变大小具有一些最大的影响。我们预计我们的研究将 提供对 CVD 潜在途径的更全面的了解，更好地整合人类和 小鼠数据以及对病变中巨噬细胞生长和周转的更好理解。我们充满希望 这些研究将带来新的治疗或诊断进展。