Coordinated dynamic regulation and function of IRF transcription factors

IRF转录因子的协调动态调控和功能

• 批准号: 10155390
• 负责人: Alexander Hoffmann
• 金额: $ 39万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155390
• 关键词: Address; Affect; Biological Assay; Cells; Chromatin; Complement; Complex; Data; Dose; Enhancers; Feedback; Gene Expression; Genes; Genetic; Goals; IRF3 gene; Immune; Immune signaling; Immunologic Memory; Innate Immune Response; Interferon Type I; Interferons; Measurement; Mediating; Modeling; Molecular; Play; Recording of previous events; Regulation; Resolution; Role; Secondary to; Shapes; Signal Transduction; Stimulus; System; Testing; Time; Viral; autocrine; base; genome-wide; macrophage; mathematical model; member; novel; paracrine; pathogen; pathogen exposure; programs; response; tool; transcription factor; viral resistance

Project Summary/Abstract Innate immune signaling by macrophages is critical as the first response to pathogen exposure. Three Interferon-regulatory factors (IRFs) are the critical regulators of the innate immune response (namely IRF3, ISGF3, and IRF7), and they respond to pathogen exposure coordinately and interdependently. How these IRFs function as a regulatory system, and what their specific roles are in regulating the extensive gene expression programs comprising hundreds of genes, has remained unclear, as previous assays lacked resolution to quantitate IRF dynamics at single cell resolution, and interdependencies between these factors could not be delineated by prevailing models. Thus the scientific premise of the proposed studies is that utilizing cutting-edge quantitative single cell and genome-wide measurements will allow us develop a quantitative mathematical model that delineates respective functions of IRF3, ISGF3, IRF7. We will address this goal with the following Aims: In Aim 1, we will elucidate the mechanism that are able to produce the complex dynamic control of the primary response factor IRF3 that we reveal in our preliminary studies. In Aim 2, we will investigate the functional consequence of differential, pathogen-specific IRF3 dynamics on chromatin control and target gene expression. In Aim 3, we will develop a predictive signaling model of the dose response and dynamic control of ISGF3 activated via autocrine and paracrine type I interferon secretion, and characterize how it contributes to innate immune gene expression in both infected and in bystander cells. In Aim 4, we will examine the regulatory control of IRF7 and test the hypothesis that it plays a key role in determining innate immune responses in previously interferon-`warned' cells, thus mediating a form of innate immune memory.

项目摘要/摘要 巨噬细胞的先天免疫信号传导至关重要，因为对病原体暴露的第一反应。三 干扰素调节因子（IRF）是先天免疫反应的关键调节剂（即IRF3， ISGF3和IRF7），它们对病原体的暴露对病原体的反应进行了协调和相互依存的反应。这些如何 IRFS充当调节系统，以及它们在调节广泛基因方面的特定作用 包含数百个基因的表达程序仍不清楚，因为先前缺乏的测定 在单细胞分辨率下定量IRF动力学的分辨率以及这些因素之间的相互依存关系 无法通过流行的模型来描绘。 因此，拟议研究的科学前提是利用尖端的定量单细胞和 全基因组测量结果将使我们开发一个定量数学模型，以描绘 IRF3，ISGF3，IRF7的各自功能。我们将以以下目的解决这个目标： 在AIM 1中，我们将阐明能够产生初级复杂动态控制的机制 我们在初步研究中揭示的响应因子IRF3。 在AIM 2中，我们将研究差异，病原体特异性IRF3动力学的功能后果 染色质控制和靶基因表达。 在AIM 3中，我们将开发一个剂量响应的预测信号传导模型和ISGF3的动态控制 通过自分泌和旁分泌I型干扰素分泌激活，并表征其对先天性的贡献 受感染和旁观者细胞中的免疫基因表达。 在AIM 4中，我们将检查IRF7的调节控制，并检验它在其中起关键作用的假设 确定先前干扰素中的先天免疫反应，从而介导一种先天的形式 免疫记忆。