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.

项目摘要/摘要 树突状细胞（DCS）在靶向对病原体的免疫反应中起关键作用，均通过起作用 抗原表现出细胞，并通过分泌有效的先天免疫和炎症细胞因子。他们有区别 从在骨髓中发现的造血干细胞到多种亚型，具有更多的亚型 炎症/适应性免疫或更多先天免疫功能。这些差异的不利 过程是骨髓增生性疾病（MPD）的根本原因，包括急性髓样白血病（AML）， 以及炎症性疾病兰格汉细胞组织细胞增多症（LCH）。这些差异化过程可能是 具有关键的髓样分化和生长因子GM-CSF和FLT3L的概括的离体，并且先前的工作具有 表明NFKAPPAB信号系统是重要的调节器。但是，鉴于这种多重的复杂性 转录因子，多调节器信号传导系统，其在亚型分化，增殖中的作用，并在 疾病的理解仍然很差。 在拟议的项目中，我们将研究NFKappab控制在协调差异化计划中的作用 树突状细胞成两个发育途径。根据我们的初步结果，我们提出了 总体假设，即DC期间NFKappab信号系统的正确逐步组装 分化途径对于平差增殖和成熟至关重要。而古典的ikappabalpha，-beta，-epsilon Mediate 瞬态NFKAPPAB炎症反应，最近描述的Ikappabsome扮演着重要的缓冲和 在DC分化中的协调作用。 ikappabsome的正调导致严重但令人惊讶的不同 两个DC发育途径中的表型。 我们将在树突状细胞期间结合一个经过实验验证的NFKAPPAB信号的数学模型 分化和功能，具有定量的生化，流式细胞术和活细胞荧光 显微镜，干涉法和谱系跟踪研究，涉及敲蛋白报道小鼠和许多新型 遗传小鼠菌株以发现与骨髓增生相关的NFKAPPAB失调的分子基础 疾病（MPD）和Langerhans细胞组织细胞增多症（LCH）。我们将应用有关Ikappabsome的这些见解 调节以检查患者样本以及潜在药物靶标的功效和风险。

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