Structure and Function of Immune Gene Regulatory Networks

项目摘要 基因调控网络（GRNs）是几乎所有生物过程的核心。研究 在我的实验室，重点是了解人类GRNs的结构和逻辑， 制定治疗干预战略的最终目标。我们目前的差距 对GRNs的理解包括：确定转录因子（TF）的组合如何 调节特定的靶基因表达模式，确定不同的机制， 基因共同调节以影响给定的生物反应，决定GRNs如何重新连接 对环境线索的反应，并设计策略来操纵GRNs来调节 生物学成果。细胞因子为研究GRNs提供了一个理想的模型系统， 基因在转录水平上受到高度调控，因为这种调控涉及一种 细胞类型特异性TF和由不同信号传导激活的TF之间的复杂相互作用 途径。在这个建议中，我们将研究细胞因子的结构和调控逻辑 GRN通过整合互补方法来绘制蛋白质-DNA相互作用，功能 扰动和表型特征。此外，我们将通过以下方式确定机制 所述病毒编码的TF通过确定靶向细胞因子而干扰细胞因子GRN 调节区和靶向宿主蛋白如TF、辅因子和信号蛋白。 总的来说，拟议的研究将确定一般原则，并提出一个研究框架 并操纵GRNs，这将最终导致影响人类健康的新策略。

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.