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Structure and Function of Immune Gene Regulatory Networks

免疫基因调控网络的结构和功能

基本信息

批准号：
10620447
负责人：
Juan Ignacio Fuxman Bass
金额：
$ 44.55万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620447
关键词：
Affect Binding Biological Biological Assay Biological Process Cell Proliferation Cells Cues Cytokine Gene DNA Viruses Data Set Disease Double Stranded DNA Virus Foundations Gene Expression Gene Expression Profile Genes Genetic Transcription Genome Goals Human Hybrids Immune Immune Evasion Immune System Diseases Immune response Immunosuppression Individual Laboratories Logic Metabolic Modeling Outcome Play Productivity Promoter Regions Regulation Regulatory Element Reporter Research Retroviridae Role Specificity Structure Therapeutic Transcriptional Regulation Viral Viral Genes Viral Genome Viral Physiology Virus Virus Diseases Virus Latency Virus Replication Yeasts cell type cytokine design gene regulatory network genetic manipulation genome-wide immune function immunoregulation novel novel therapeutic intervention pathogen programs protein protein interaction response transcription factor

项目摘要

PROJECT SUMMARY Gene regulatory networks (GRNs) involving interactions between transcription factors (TFs) and cis- regulatory elements (CREs) are central to most biological processes. Research in my laboratory aims to characterize the structure and logic of human GRNs with the ultimate goal of devising therapeutic strategies. Current gaps in our understanding of GRNs include: determining how TF combinations provide transcriptional specificity, determining how GRNs are rewired in response to environmental cues and pathogens, and designing strategies to manipulate GRNs to modulate biological outcomes. Cytokines present an archetype model to study GRNs because cytokines genes are highly regulated at the transcriptional level in different cell types and stimulation conditions. We have recently delineated a large- scale cytokine GRN by determining the binding of individual TFs to cytokine promoter regions and integrating with expression datasets. Here, we will expand these studies to identify the role of heterodimeric TFs in cytokine regulation by integrating TF-wide screens using a novel heterodimer yeast one-hybrid approach we developed, and multi-CUT&tag to profile TF heterodimer binding genome-wide. This will identify the rules by which heterodimers confer transcriptional specificity and will provide targets for modulation of cytokine expression in disease. Viruses can rewire or leverage host GRNs for productive viral replication and to evade immune responses. Given the coexistence of viral genomes and host TFs and host genomes and viral TF within infected cells, this provides the opportunity for viral-host cross- transcriptional regulation. For example, CREs of DNA viruses and retroviruses can bind host TFs to regulate viral gene expression in the appropriate cell types and states to promote viral replication or latency. We will identify the viral CREs from dsDNA viruses and retroviruses that are active in different cell types and activation states using high-throughput reporter assays, as well as the human TFs that regulate these viral CREs. Viral TFs can bind to host CREs to modulate the expression of host genes to promote cell proliferation, metabolic changes, and immune suppression. We will continue to characterize the function of viral TFs including identifying targets, transcriptional activity, protein-protein interactions, and changes in transcriptional programs. Altogether, the proposed studies will identify general principles and generate a framework to study and manipulate immune GRNs, and will identify mechanisms by which viruses control host GRNs to replicate and evade immune responses.

项目摘要基因调控网络（GRNs）涉及转录因子（TF）和顺式- 调节元件（克雷斯）是大多数生物过程的中心。我实验室的研究旨在描述人类GRN的结构和逻辑，最终目标是设计治疗方法战略布局目前我们对GRNs的理解存在的差距包括：确定TF组合如何提供转录特异性，决定GRNs如何响应环境线索而重新连接，病原体，并设计策略来操纵GRNs来调节生物学结果。细胞因子提出了一个研究GRNs的原型模型，因为细胞因子基因在GRNs中受到高度调节，在不同的细胞类型和刺激条件下的转录水平。我们最近描绘了一个巨大的- 通过确定单个TF与细胞因子启动子区的结合来缩放细胞因子GRN，与表达式数据集集成。在这里，我们将扩大这些研究，以确定的作用，通过使用新型异源二聚体酵母整合TF-宽筛选的异源二聚体TF在细胞因子调节中的作用我们开发的单杂交方法和多CUT &标签来分析TF异源二聚体结合基因组范围。这将确定异二聚体赋予转录特异性的规则，并将提供靶点。用于调节疾病中的细胞因子表达。病毒可以重新连接或利用主机GRN，病毒复制和逃避免疫反应。鉴于病毒基因组和宿主TF的共存以及宿主基因组和感染细胞内的病毒TF，这为病毒-宿主交叉提供了机会。转录调控例如，DNA病毒和逆转录病毒的克雷斯可以结合宿主TF，在适当的细胞类型和状态中调节病毒基因表达以促进病毒复制，或延迟。我们将从dsDNA病毒和逆转录病毒中鉴定在不同细胞中有活性的病毒克雷斯使用高通量报告分析，以及调节人TF的人TF，这些病毒性克雷斯。病毒TF可以与宿主克雷斯结合以调节宿主基因的表达，从而促进细胞的增殖。细胞增殖、代谢变化和免疫抑制。我们将继续描述病毒转录因子的功能，包括识别靶点、转录活性、蛋白质-蛋白质相互作用，转录程序的变化。总之，拟议的研究将确定一般原则，产生一个框架来研究和操纵免疫GRNs，并将确定机制，病毒控制宿主GRN复制和逃避免疫应答。