Understanding dynamical coding by NFkB

通过 NFkB 理解动态编码

• 批准号: 9223713
• 负责人: Alexander Hoffmann
• 金额: $ 61.07万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223713
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Baltimore; Biological; Biological Models; Carrying Capacities; Cell Survival; Cell division; Cell surface; Cells; Code; Computer Analysis; Computer Simulation; Data; Data Analyses; Data Set; Dose; Effectiveness; Ensure; Enzyme-Linked Immunosorbent Assay; Exposure to; Feedback; Gene Expression; Gene Targeting; Genes; Genetic Models; Genetic Transcription; Half-Life; Human Pathology; Immune; Immune signaling; Immunity; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Laboratories; Ligands; Measures; Mediating; Messenger RNA; Methodology; Methods; Microfluidics; Modeling; Noise; Nuclear; Pathologic; Peptide Hydrolases; Population; Recruitment Activity; Regimen; Regulator Genes; Resolution; Signal Transduction; Signaling Protein; Site; Specific qualifier value; Specificity; Stimulus; System; Technology; Therapeutic; Tissues; Toxic effect; Work; c new; cancer therapy; cell type; cellular transduction; chemokine; cohort; cytokine; gene product; improved; information processing; mathematical model; mutant; network models; new therapeutic target; novel; pathogen; programs; promoter; public health relevance; response; single cell proteins; transcription factor; transcriptome sequencing

 DESCRIPTION (provided by applicant): Inflammation is critical for immunity but it is also a key determinant of a large number of human pathologies, if not as cause, then as promoter of progression. The expression of hundreds of genes is induced during inflammation, encompassing pro-inflammatory cytokines that function systemically, chemokines that recruit specific cell types to the site of infection, cell surface proteases for local tissue remodeling, itra-cellular innate immune effectors, regulators of cell survival and division, anti-inflammatory mediators and numerous signaling proteins that determine the progression of the inflammatory response and cellular responsiveness. Indeed, each pathologic threat, injury or inflammatory insult requires an appropriate and specific blend of these gene products to maximize the effectiveness of the inflammatory response and minimize its toxicity. Inflammatory responses are described as being stimulus-specific, mediated by stimulus-specific gene expression programs. It is well established that NFκB is the key regulator of inflammatory gene expression, and that the control of NFκB activity is highly dynamic due to several prominent delayed negative feedback loops. Prompted by our finding that NFκB dynamics are stimulus-specific, we posited the hypothesis that NFκB dynamics constitute a signaling code. According to this hypothesis, the dynamics of NFκB activity encode information about the stimulus that is then decoded by the nuclear gene regulatory network to produce stimulus-specific gene expression. While much progress has been made in elucidating the stimulus-encoding mechanisms, it has been remarkably difficult to develop a mechanistic understanding of how gene regulatory networks may decode stimulus-specific NFκB dynamics to produce stimulus-specific gene expression. Some reasons for the slow progress are the large numbers of possible stimulation conditions and the substantial cell-to-cell variability in NFκB dynamics - these necessitate high throughput single studies and novel data analysis approaches. Here we will combine (a) experimentally validated mathematical models (Hoffmann), (b) comprehensive microfluidics-enabled experimentation (Tay), and (c) new information theoretic approaches (Wollman) to (i) identify the dynamical features that mediate stimulus-specific cellular responses, (ii) quantify their reliability and information carrying capacity, and (iii) determine the gene regulatory strategies that decode these specific NFκB dynamical features. As a concerted collaborative effort, the proposed work will break through the current impasse in understanding how inflammatory gene expression programs are specified, thus revealing novel opportunities for therapeutic modulation in myriad pathologic settings. Further, as a model system for the field of signal transduction in general, the work will have broad impact in establishing concepts and workflow for the analysis of dynamical codes found also in other biological signaling systems.

 描述（由申请人提供）：炎症对免疫力至关重要，但它也是大量人类病理学的关键决定因素，如果不是原因，则是进展的促进因素。在炎症过程中诱导数百种基因的表达，包括全身发挥作用的促炎细胞因子、将特定细胞类型募集到感染部位的趋化因子、用于局部组织重塑的细胞表面蛋白酶、细胞内先天免疫效应物、细胞存活和分裂的调节剂，抗炎介质和许多决定炎症反应和细胞反应进展的信号蛋白。事实上，每一种病理威胁、损伤或炎性损伤都需要这些基因产物的适当和特定的混合，以使炎症反应的有效性最大化并使其毒性最小化。炎症反应被描述为刺激特异性的，由刺激特异性基因表达程序介导。已经确定NFκB是炎症基因表达的关键调节因子，并且由于几个显著的延迟负反馈环，NFκB活性的控制是高度动态的。基于我们发现NFκB动力学是刺激特异性的，我们假设NFκB动力学构成了一个信号密码。根据这一假设，NFκB活性的动态编码有关刺激的信息，然后由核基因调控网络解码，产生刺激特异性基因表达。虽然在阐明刺激编码机制方面已经取得了很大进展，但对于基因调控网络如何解码刺激特异性NFκB动力学以产生刺激特异性基因表达的机制理解仍然非常困难。进展缓慢的一些原因是大量可能的刺激条件和NFκB动力学中的大量细胞间变异性-这些需要高通量的单一研究和新的数据分析方法。在这里，我们将结合联合收割机（a）实验验证的数学模型（Hoffmann），（B）全面的微流体使能实验（Tay），和（c）新的信息理论方法（Wollman），以（i）识别介导刺激特异性细胞反应的动力学特征，（ii）量化它们的可靠性和信息承载能力，以及（iii）确定解码这些特定NFκB动力学特征的基因调控策略。作为一个协调一致的合作努力，拟议的工作将突破目前的僵局，了解炎症基因表达程序是如何指定的，从而揭示了新的机会，治疗调制在无数的病理设置。此外，作为一般信号转导领域的模型系统，这项工作将在建立概念和工作流程方面产生广泛的影响，用于分析在其他生物信号系统中也发现的动态代码。