NFkB dynamics in the stimulus specificity of trained immunity

训练免疫刺激特异性中的 NFkB 动态

• 批准号: 10429836
• 负责人: Quen J Cheng
• 金额: $ 20.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429836
• 关键词: Address; Adoptive Transfer; Anti-Inflammatory Agents; Binding; Bioinformatics; Candida albicans; Cell Nucleus; Cells; ChIP-seq; Chromatin; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Communicable Diseases; DNA; Diagnostic; Elements; Enhancers; Environment; Epigenetic Process; Exposure to; Faculty; Gene Expression; Genes; Genus Mycobacterium; Glucans; Goals; Grant; Immune; Immune Response Genes; Immune response; Immunity; Immunologic Memory; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; International; K-Series Research Career Programs; Knock-out; Ligands; Measures; Mediating; Memory; Mentors; Mentorship; Molecular; Mus; Nucleosomes; Pattern; Phagocytosis; Phenotype; Physicians; Predisposition; Principal Investigator; Psychological Transfer; Regulation; Rest; Science; Scientist; Secondary to; Shapes; Specificity; Stimulus; Testing; Therapeutic; Time; Tissue Sample; Training; Training Support; cytokine; differential expression; epigenome; epigenomics; helminth infection; histone modification; in vivo; in vivo evaluation; macrophage; member; monocyte; mouse model; pathogen; pathogenic fungus; promoter; receptor; response; secondary infection; senior faculty; symposium; tool; transcription factor

PROJECT SUMMARY / ABSTRACT Cells of the innate immune system such as monocytes and macrophages can be reprogrammed by their environmental context. Stimuli in the environment, such as cytokines and pathogen-associated molecules, can dramatically alter cellular phenotype. This phenomenon, termed “trained immunity,” is driven by epigenetic changes to the enhancer repertoire. Upon stimulation, transcription factors such as NFκB can bind to closed chromatin regions, open the chromatin, and facilitate histone modification, activating previously silent regulatory DNA elements called latent enhancers. These epigenetically reprogrammed innate immune cells respond differently to subsequent stimulation and alter host responses to infectious diseases. Interestingly, the effects of trained immunity are variable. In some cases, trained immunity primes the host to produce an increased inflammatory response upon secondary stimulation, but in other cases it diminishes the inflammatory response. Whether reprogrammed monocytes produce increased or diminished inflammatory responses depends on what stimulus forms the memory. That is, the effects of trained immunity are stimulus- specific. However, the mechanisms that account for this stimulus-specificity are unclear, and understanding these mechanisms will be critical for harnessing the therapeutic potential of trained immunity. The central hypothesis of this grant is that different dynamic features of NFκB activity contribute to the stimulus- specificity of trained immunity. NFκB is a ubiquitous transcription factor that is considered the master regulator of inflammatory gene expression. Although nearly all pathogens and cytokines activate NFκB, they do so with varying dynamics. In particular, some stimuli induce an oscillatory pattern of activity, while others induce a non- oscillatory pattern of activity. We have shown that non-oscillatory NFκB results in more de novo enhancers than oscillatory NFκB using a mouse model in which NFκB oscillations are perturbed. Aim 1 of this proposal characterizes the stimulus-specificity of training in vivo and tests the hypothesis that trained immunity produced by different NFκB dynamics differentially alters host response to secondary infection with Candida albicans. Aim 2 investigates the mechanisms by which NFκB dynamics-dependent enhancers regulate gene expression. This mentored career development award will support the training of a promising junior faculty member at UCLA. The specific training objectives are to acquire expertise in 1) bioinformatics, 2) mouse models of infection, 3) immune profiling of tissue samples, and 4) the field of innate immune memory. Training will occur through mentorship by senior faculty members, coursework, seminars, and international conferences. The goal of this career development award is to establish the principal investigator as an independent physician-scientist, ultimately producing diagnostic and therapeutic tools for immune-mediated complications of infectious diseases.

项目摘要 /摘要 先天免疫系统（例如单核细胞和巨噬细胞）的细胞可以通过其重新编程 环境环境。环境中的刺激，例如细胞因子和病原体相关的分子，可以 动态改变细胞表型。这种现象称为“受过训练的免疫”，由表观遗传驱动 更改增强器曲目。刺激后，诸如NFκB之类的转录因子可以与封闭 染色质区域，打开染色质并促进组蛋白修饰，激活先前无声调节 DNA元素称为潜在增强剂。这些表观遗传重编程的先天免疫细胞反应 与随后的刺激和改变宿主对传染病的反应不同。 有趣的是，受过训练的免疫共同体的影响是可变的。在某些情况下，训练有训练 继发刺激后产生了增加的炎症反应，但在其他情况下，它会减少 炎症反应。重编程的单核细胞是否会增加或减少炎症 响应取决于什么刺激形成记忆。也就是说，受过训练的免疫的影响是刺激 具体的。但是，解释这种刺激特异性的机制尚不清楚，并且理解 这些机制对于利用受过训练的免疫力的治疗潜力至关重要。 该赠款的中心假设是NFκB活性的不同动态特征有助于刺激 受过训练的免疫的特异性。 NFκB是无处不在的转录因子，被认为是主调节器 炎症基因表达。尽管几乎所有的病原体和细胞因子都激活NFκB，但它们会使用 不同的动态。特别是，某些刺激引起了活性的振荡模式，而另一些刺激诱导了非 - 活动的振荡模式。我们已经表明，非振荡的NFκB导致从头增强子多于 使用NFκB振荡扰动的小鼠模型的振荡NFκB。目的1本提案 表征体内训练的刺激特异性，并检验了训练的免疫学的假设 通过不同的NFκB动力学对白色念珠菌对继发感染的反应有所不同。目的 2研究了NFκB动力学依赖性增强子调节基因表达的机制。 这项修订的职业发展奖将支持加州大学洛杉矶分校的一名少年教师的培训。 具体的培训目标是获得1）生物信息学的专业知识，2）小鼠感染模型，3） 组织样品的免疫分析和4）先天免疫记忆的领域。培训将通过 高级教职员工，课程，半手赛和国际会议的指导。目标的目标 职业发展奖是为了建立主要研究员，成为独立的身体科学家， 最终产生用于免疫介导的传染病并发症的诊断和治疗工具。