The NFkB System in Dendritic Cells

树突状细胞中的 NFkB 系统

• 批准号: 10375381
• 负责人: Alexander Hoffmann
• 金额: $ 41.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-03 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375381
• 关键词: Acute Myelocytic Leukemia; Animals; Antigen-Presenting Cells; Biochemical; Bone Marrow; Buffers; Cell Culture Techniques; Cell Death; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Clinical; Complex; Coupling; Dendritic Cell Pathway; Dendritic Cells; Dependence; Development; Disease; Drug Targeting; Eosinophilic Granuloma; Epigenetic Process; Equilibrium; Event; FLT3 gene; FLT3 ligand; Fluorescence Microscopy; Genetic; Genetic study; Giant Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Hematopoietic stem cells; Homeostasis; Human; I Kappa B-Alpha; Immune; Immune Targeting; Immune response; Inflammatory; Inflammatory Response; Interferometry; Interferon Type II; Kinetics; Knock-in; Malignant Neoplasms; Measurement; Mediating; Modeling; Molecular; Molecular Weight; Mouse Strains; Mus; Mutant Strains Mice; Myelogenous; Myelopoiesis; Myeloproliferative disease; Pathway interactions; Patients; Pharmacology; Phase; Phenotype; Plant Roots; Play; Process; Publishing; Regulation; Reporter; Resolution; Risk; Role; Sampling; Signal Transduction; System; Systems Biology; Testing; Therapeutic; Work; acute myeloid leukemia cell; base; chronic inflammatory disease; cytokine; dimer; hematopoietic stem cell differentiation; human disease; immune function; inhibitor; innate immune function; insight; leukemia; live cell microscopy; mathematical model; morphogens; network models; novel; pathogen; predictive modeling; programs; response; transcription factor

Project Summary/Abstract Dendritic cells (DCs) play key roles in targeting immune responses to pathogens, both by functioning as antigen presenting cells and by secreting potent innate immune and inflammatory cytokines. They differentiate from hematopoietic stem cells found in the bone marrow into multiple subtypes that have more inflammatory/adaptive immune or more innate immune functions. Misregulation of these differentiation processes is the root cause of myeloproliferative disorders (MPD) including acute myeloid leukemia (AML), and the inflammatory disease Langerhans Cell Histiocytosis (LCH). These differentiation processes may be recapitulated ex vivo with key myeloid differentiation and growth factors GM-CSF and Flt3L, and prior work has shown that the NFkappaB signaling system is an important regulator. Yet given the complexity of this multi- transcription factor, multi-regulator signaling system, its roles in subtype-differentiation, proliferation, and in disease remain poorly understood. In the proposed project we will examine the role of NFkappaB control in coordinating differentiation programs of dendritic cells into two developmental pathways. Based on our preliminary results we propose the overarching hypothesis that proper stepwise assembly of the NFkappaB signaling system during DC differentiation pathways is critical for phasing proliferation and maturation; while classical IkappaBalpha, -Beta, -epsilon mediate transient NFkappaB inflammatory responses, the recently described IkappaBsome plays a critical buffering and coordinating role in DC differentiation. Misregulation of the IkappaBsome leads to severe but surprisingly different phenotypes in the two DC developmental pathways. We will combine an experimentally validated mathematical model of NFkappaB signaling during dendritic cell differentiation and function, with quantitative biochemical, flow cytometric, and live cell fluorescence microscopy, interferometry and lineage tracking studies involving knockin reporter mice, and a number of novel genetic mouse strains to uncover the molecular basis of NFkappaB misregulation associated with myeloprolferative disorders (MPD) and Langerhans Cell Histiocytosis (LCH). We will apply these insights about the IkappaBsome regulation to examine patient samples and the efficacy and risks of potential drug targets.

项目总结/摘要 树突状细胞（DC）在靶向病原体的免疫应答中发挥关键作用， 抗原呈递细胞和分泌有效的先天免疫和炎性细胞因子。它们分化 从骨髓中发现的造血干细胞分化为多种亚型， 炎症/适应性免疫或更多先天免疫功能。这些分化的失调 过程是骨髓增生性疾病（MPD）的根本原因，包括急性髓性白血病（AML）， 和炎性疾病朗格汉斯细胞组织细胞增生症（LCH）。这些分化过程可能是 用关键的髓样分化和生长因子GM-CSF和Flt 3L进行体外概括，先前的工作已经 表明NF κ B信号系统是一个重要的调节器。然而，鉴于这一多方面的复杂性， 转录因子，多调节信号系统，其在亚型分化，增殖， 疾病仍然知之甚少。 在拟议的项目中，我们将研究NF κ B控制在协调分化程序中的作用， 树突状细胞分为两种发育途径。根据我们的初步结果，我们提出了 总体假设，在DC期间NF κ B信号系统的适当逐步组装 分化途径对于分阶段增殖和成熟至关重要;而经典的IkappaB α，β，β-介导 瞬时NF κ B炎症反应，最近描述的IkappaBsome起着关键的缓冲作用， 在DC分化中的协调作用。IkappaBsome的失调导致了严重的但令人惊讶的不同 两种DC发育途径中的表型。 我们将联合收割机结合一个实验验证的树突状细胞过程中NF κ B信号传导的数学模型， 分化和功能，定量生化，流式细胞仪，和活细胞荧光 显微镜，干涉测量和谱系跟踪研究涉及敲入报告小鼠，和一些新的 遗传小鼠品系，以揭示与骨髓增生相关的NF κ B失调的分子基础 疾病（MPD）和朗格汉斯细胞组织细胞增生症（LCH）。我们将应用这些关于IkappaBsome的见解 该法规旨在检查患者样本以及潜在药物靶点的疗效和风险。

项目成果

NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.

RelB 表达减少导致 NFκB 通路失调，导致严重的自身免疫性疾病和免疫力下降。

• DOI: 10.1016/j.jaut.2022.102946
• 发表时间: 2023
• 期刊: Journal of autoimmunity
• 影响因子: 12.8
• 作者: Sharfe,Nigel;Dalal,Ilan;Naghdi,Zahra;Lefaudeux,Diane;Vong,Linda;Dadi,Harjit;Navarro,Hector;Tasher,Diana;Ovadia,Adi;Zangen,Tzili;Ater,Dorit;Ngan,Bo;Hoffmann,Alexander;Roifman,ChaimM
• 通讯作者: Roifman,ChaimM

RelB-deficient autoinflammatory pathology presents as interferonopathy, but in mice is interferon-independent.

RelB 缺陷的自身炎症病理表现为干扰素病，但在小鼠中是不依赖干扰素的。

• DOI: 10.1016/j.jaci.2023.06.024
• 发表时间: 2023
• 期刊: The Journal of allergy and clinical immunology
• 作者: Navarro,HéctorI;Liu,Yi;Fraser,Anna;Lefaudeux,Diane;Chia,JenniferJ;Vong,Linda;Roifman,ChaimM;Hoffmann,Alexander
• 通讯作者: Hoffmann,Alexander