The NFkB System in Dendritic Cells

树突状细胞中的 NFkB 系统

• 批准号: 9891942
• 负责人: Alexander Hoffmann
• 金额: $ 43.43万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891942
• 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; Differentiation and Growth; Disease; Drug Targeting; Eosinophilic Granuloma; Epigenetic Process; Equilibrium; Event; FLT3 ligand; Fluorescence Microscopy; Genetic; Genetic study; Giant Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Hematopoietic stem cells; Homeostasis; Human; 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/antagonist; innate immune function; insight; leukemia; live cell microscopy; mathematical model; 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 NFB 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 NFB 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 NFB signaling system during DC differentiation pathways is critical for phasing proliferation and maturation; while classical IB, -, - mediate transient NFB inflammatory responses, the recently described IBsome plays a critical buffering and coordinating role in DC differentiation. Misregulation of the IBsome leads to severe but surprisingly different phenotypes in the two DC developmental pathways. We will combine an experimentally validated mathematical model of NFB 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 NFB misregulation associated with myeloprolferative disorders (MPD) and Langerhans Cell Histiocytosis (LCH). We will apply these insights about the IBsome 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 过程是髓样白血病（AML）的根本原因， 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NFB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 疾病仍然很了解。 在拟议的项目中，我们将研究NFB控制在协调区分程序中的作用 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 总体假设是DC期间NFB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ib，-， - 中介 瞬态NFB炎症反应，最近描述的I泡沫起着关键的缓冲和 DC分化中的协调作用。 I泡沫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NFB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，干扰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的NFB失误的分子基础 疾病（MPD）和Langerhans细胞组织细胞增多症（LCH）。我们将应用这些有关IBlosome的见解 调节以检查患者样本以及潜在药物靶标的效率和风险。