Structure and Function of Immune Gene Regulatory Networks

免疫基因调控网络的结构和功能

• 批准号: 10226062
• 负责人: Juan Ignacio Fuxman Bass
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226062
• 关键词: Biological; Biological Models; Biological Process; Cell Differentiation process; Complex; Cues; Cytokine Gene; DNA-Protein Interaction; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Health; Homeostasis; Human; Immune; Laboratories; Lead; Logic; Maps; Methods; Nucleic Acid Regulatory Sequences; Outcome; Pathogenicity; Phenotype; Proteins; Regulation; Regulator Genes; Research; Signal Pathway; Signaling Protein; Structure; Therapeutic Intervention; Viral; cell type; cofactor; cytokine; design; immune function; immunoregulation; novel strategies; novel therapeutic intervention; response; transcription factor

PROJECT SUMMARY Gene regulatory networks (GRNs) are central to almost all biological processes. Research in my laboratory focusses on understanding the structure and logic of human GRNs with the ultimate goal of devising strategies for therapeutic interventions. Current gaps in our understanding of GRNs include: determining how combinations of transcription factors (TFs) regulate specific target gene expression patterns, identifying mechanisms by which different genes are co-regulated to effect a given biological response, determining how GRNs are rewired in response to environmental cues, and designing strategies to manipulate GRNs to modulate biological outcomes. Cytokines present an ideal model system to study GRNs because cytokines genes are highly regulated at the transcriptional level and because this regulation involves a complex interplay between cell type-specific TFs and TFs activated by different signaling pathways. In this proposal, we will investigate the structure and regulatory logic of the cytokine GRN by integrating complementary methods to map protein-DNA interactions, functional perturbations, and phenotypic characterizations. Further, we will determine the mechanisms by which virally-encoded TFs perturb the cytokine GRN by determining the targeted cytokine regulatory regions and targeted host proteins such as TFs, cofactors, and signaling proteins. Overall, the proposed studies will identify general principles and generate a framework to study and manipulate GRNs which will ultimately lead to novel strategies impacting human health.

项目摘要 基因调节网络（GRN）几乎是所有生物过程的核心。研究 在我的实验室中，专注于理解人类grns的结构和逻辑 制定治疗干预策略的最终目标。当前的差距 对GRN的了解包括：确定转录因子的组合（TFS）如何 调节特定靶基因表达模式，识别不同的机制 基因共同调节以实现给定的生物学反应，确定GRN的重新连接方式 响应环境线索，并设计策略以操纵GRN来调节 生物结果。细胞因子提出了研究GRN的理想模型系统，因为细胞因子 基因在转录水平上受到高度调节，因为该调节涉及 通过不同信号激活的细胞类型特异性TF和TF之间的复杂相互作用 途径。在此提案中，我们将研究细胞因子的结构和调节逻辑 通过将互补方法整合到绘制蛋白-DNA相互作用，功能性的GRN 扰动和表型特征。此外，我们将通过 哪些病毒编码的TF通过确定靶向细胞因子来扰动细胞因子GRN 调节区域和靶向宿主蛋白，例如TFS，辅因子和信号蛋白。 总体而言，拟议的研究将确定一般原则并生成一个研究框架 并操纵GRN，最终会导致影响人类健康的新型策略。