NFkB Signaling in Macrophages

巨噬细胞中的 NFkB 信号转导

基本信息

批准号：
10054972
负责人：
Alexander Hoffmann
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-17 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054972
关键词：
Adipose tissue Biochemical Biological Process Bone Marrow Cell Nucleus Cells Characteristics Chromatin Clinical Computer Models Data Disease Disease model Endotoxins Environmental Risk Factor Epigenetic Process Exposure to Family Family member Funding Gene Expression Genes Genetic Half-Life I Kappa B-Alpha Inflammation Inflammatory Interferon Type II Knock-in Knock-out Lead Lesion Ligands Link Liver MAP Kinase Gene Measures Messenger RNA Modeling Molecular Mus Mutation Obesity Pathogenesis Pathologic Pathology Pathway interactions Pattern Pharmacology Physiological Play Population Study Predisposition Regulation Reporter Role Signal Transduction Stimulus TNF gene Testing Therapeutic Time Venus Work autocrine base cell type cytokine epigenomics genetic variant live cell microscopy macrophage mathematical model mouse model p38 Mitogen Activated Protein Kinase pathogen preservation programs promoter response tissue culture tissue injury transcription factor

项目摘要

ABSTRACT Inflammatory signaling by macrophages in response to pathogens or tissue injury is the key determinant of the pathology and pathogenesis of infectious and non-infectious disease. The transcription factor NFκB controls the inflammatory gene expression programs, but it remains unclear how its regulation determines healthy or disease-associated gene expression responses. During the previous funding period, we have used a combined experimental / computational modeling approach to gain a predictive understanding of how NFκB is activated in response to TLR signaling and that multiple mechanisms converge to regulate NFκB. After developing a live cell microscopy tracking workflow we discovered that contrary to previous notions NFκB dynamics are highly oscillatory. By generating a knockin RelA-Venus mouse, we are able – for the first time – measure NFκB dynamics in primary cells revealing oscillations as an intrinsic hallmark of NFκB in healthy macrophages. Based on preliminary studies, we propose to test the hypothesis that NFκB oscillations are critical for healthy macrophage functions as they preserve their epigenetic chromatin state. Non-oscillatory NFκB is more likely to alter the macrophage-characteristic chromatin state and lead to altered, disease-associated gene expression. Further, while oscillations are pervasive, their duration is modulated by different stimuli, allowing for differential, stimulus-specific gene expression programs. Together, the proposed studies will substantially contribute to our understanding of how NFκB dynamic control determines physiological and pathological gene expression programs.

抽象的巨噬细胞对病原体或组织损伤的炎症信号传导是转录因子NFκB对照炎症基因表达程序，但尚不清楚其调节如何决定健康或疾病相关的基因表达反应。在上一个资金期间，我们使用了合并的实验 /计算建模通过对TLR信号转导激活NFκB的预测理解的方法多种机制会收敛以调节NFκB。在开发了活细胞显微镜跟踪工作流程后，我们发现与以前的音符对比NFκB动力学是高度振荡的。通过产生敲击 Rela-Venus小鼠，我们首次能够测量原始细胞中的NFκB动力学揭示振荡是健康巨噬细胞中NFκB的内在标志。根据初步研究，我们建议检验NFκB振荡对于健康至关重要的假设巨噬细胞在保留其表观遗传染色质状态时起作用。非振荡NFκB的可能性更大改变巨噬细胞特征染色质状态并导致疾病相关的基因改变表达。此外，尽管振荡无处不在，但其持续时间是通过不同的刺激调节的，允许用于差异，刺激特异性基因表达程序。共同的研究将大大有助于我们理解NFκB动态控制确定物理和病理基因表达程序。