Genomic Regulatory Networks in Innate Immune Cells

描述（由申请人提供）：了解人类先天免疫细胞如何对病原体作出反应是非常重要的，因为这些细胞通常是抵抗感染的第一道防线。最近的基因表达谱研究表明，病原体暴露导致树突状细胞和巨噬细胞的基因表达程序发生变化，但尚未揭示这些基因表达程序是如何被调节的。有了人类基因组测序和先进的全基因组分析技术，就有可能开始绘制控制宿主细胞对优先病原体感染反应的转录调控网络。这些信息将使我们能够精确地发现病原体是如何扰乱宿主细胞基因表达的，并可能为病原体控制提供新的策略。我们建议使用新开发的实验和计算技术来开始绘制控制先天免疫细胞对病原体暴露反应的转录调控网络。为实现这一目标，我们建议：1)确定人巨噬细胞和树突状细胞中关键转录调控因子的基因组靶点；2)结合全基因组定位和表达数据推断巨噬细胞和树突状细胞基因表达程序的转录调控网络；3)发现巨噬细胞和树突状细胞的转录调控网络在暴露于优先病原体时是如何被修饰的。

DESCRIPTION (provided by applicant): It is fundamentally important to understand how human innate immune cells respond to pathogens because these cells are frequently the first line of defense against infection. Recent gene expression profiling studies have shown that pathogen exposure causes changes in the gene expression programs of dendritic cells and macrophages, but have not revealed how these gene expression programs are regulated. With a sequenced human genome and advanced genome-wide analytical technologies, it is possible to begin mapping the transcriptional regulatory networks that control the host cell response to infection by priority pathogens. Such information would allow us to discover precisely how pathogens perturb host cell gene expression and might suggest new strategies for pathogen control. We propose to use newly developed experimental and computational technologies to begin mapping the transcriptional regulatory networks that control the response of innate immune cells to pathogen exposure. To accomplish this, we propose to; 1) identify the genomic targets of key transcriptional regulators in human macrophages and dendritic cells; 2) deduce the transcriptional regulatory networks that regulate macrophage and dendritic cell gene expression programs using a combination of genome-wide location and expression data; 3) discover how the transcriptional regulatory networks of macrophages and dendritic cells are modified when these cells are exposed to priority pathogens.