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.

项目总结/摘要 先天免疫系统的细胞如单核细胞和巨噬细胞可以通过其自身的免疫调节被重编程。 环境背景。环境中的刺激物，如细胞因子和病原体相关分子， 显著改变细胞表型。这种被称为“训练免疫”的现象是由表观遗传驱动的。 增强子库的变化。在刺激下，转录因子如NFκB可以与封闭的 染色质区域，打开染色质，并促进组蛋白修饰，激活以前沉默的调节 被称为潜在增强子的DNA元件。这些表观遗传重编程的先天免疫细胞 与随后的刺激不同，并改变宿主对传染病的反应。 有趣的是，训练免疫力的效果是可变的。在某些情况下，经过训练的免疫力会让宿主 在二次刺激时产生增加的炎症反应，但在其他情况下，它减少了炎症反应。 炎症反应。重编程的单核细胞是否产生增加或减少的炎性 反应取决于什么刺激形成记忆。也就是说，训练免疫力的效果是刺激- 特定.然而，解释这种刺激特异性的机制尚不清楚， 这些机制对于利用训练免疫的治疗潜力至关重要。 这项研究的中心假设是NFκB活性的不同动态特征有助于刺激- 训练免疫的特异性。NFκB是一种普遍存在的转录因子，被认为是主要的调节因子 炎性基因表达。尽管几乎所有的病原体和细胞因子都能激活NFκB，但它们与 变化的动力学。特别是，一些刺激诱导振荡模式的活动，而另一些则诱导非振荡模式的活动。 活动的振荡模式。我们已经证明，非振荡型NFκB导致更多的从头增强子， 使用NFκB振荡受到干扰的小鼠模型，观察振荡NF κB。本提案的目标1 表征了体内训练的刺激特异性，并测试了训练免疫产生的假设。 通过不同的NFκB动力学差异改变宿主对白色念珠菌继发感染的反应。目的 2研究了NFκB动力学依赖性增强子调控基因表达的机制。 这个指导职业发展奖将支持在加州大学洛杉矶分校有前途的初级教师的培训。 具体的培训目标是获得以下方面的专业知识：1）生物信息学，2）感染的小鼠模型，3） 组织样品的免疫分析，和4）先天免疫记忆领域。培训将通过 高级教师的指导，课程，研讨会和国际会议。这个目标 职业发展奖旨在将主要研究者确立为独立的医生-科学家， 最终产生用于免疫介导的感染性疾病并发症的诊断和治疗工具。