NF-kB signaling in the control of Hematopoiesis

NF-kB 信号传导在造血控制中的作用

• 批准号: 9238854
• 负责人: Chozha Vendan Rathinam
• 金额: $ 38.58万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238854
• 关键词: Acute Erythroblastic Leukemia; Acute Myelocytic Leukemia; Adult; Affect; Binding; Biochemical; Bioinformatics; Biological Assay; Biological Models; Cell Culture Techniques; Cell Cycle; Cell Transplantation; Cell physiology; Cells; Cellular biology; Computer Simulation; Cytokine Receptors; Data; Development; Disease; Dysmyelopoietic Syndromes; Employee Strikes; Engineering; Equilibrium; Gene Expression Profiling; Genetic; Genetic Transcription; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Human; Human Engineering; Immune; Impairment; Inflammatory; Interleukin-1 beta; Investigation; Knock-in Mouse; Laboratories; Link; Maintenance; Molecular; Molecular Target; Mus; Myeloid Leukemia; Myeloproliferative disease; NF-kappa B; Onset of illness; Pathologic; Pathologic Processes; Pathway interactions; Patients; Phenotype; Physiological; Production; Regulation; Research; Retrovirology; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Stem cells; Stress; TNF gene; Techniques; Testing; Transplantation; Work; Xenograft Model; base; chromatin immunoprecipitation; cytokine; exhaustion; gain of function; high risk; human disease; humanized mouse; innovation; insight; leukemia treatment; mouse model; novel; premature; prevent; public health relevance; response; self-renewal; transcription factor

Project Summary: NF-κB signaling pathway is one of the most extensively studied and understood pathways, however, the physiological impact of augmented NF-κB signaling in hematopoiesis has not been understood. Despite many recent studies documenting constitutive activation of NF-κB in patients with hematological disorders, including AML and MDS, it is remains unclear if constitutive NF-κB signaling is sufficient and/or necessary for the onset of the disease. Recently, we have shown that lack of A20 (a negative regulator of NF-κB) in hematopoietic stem cells (HSCs) causes loss of quiescence and severe hematologic abnormalities, due to constitutive NF-κB activation. In an attempt to decipher the role of NF-κB in HSCs, directly , we engineered mice to constitutively activate NF-κB in HSCs. Our preliminary data indicate that HSC quiescence and pool were completely lost, and that increased NF-κB signal alone was sufficient to disturb the transcriptional regulatory circuits of HSCs. In the proposed research, we would like to decode the potential molecular mechanisms through which increased NF-κB signals affect HSC biology. Our hypothesis is that deregulated canonical NF-κB signals impair hematopoietic stem cell (HSC) quiescence and functions by altering signal transduction pathways, `transcription factor networks' and expression of pro-inflammatory cytokines. To test this hypothesis, we will use a combination of genetic, molecular cell biology and biochemical approaches. In specific aim 1, we will decipher the intrinsic mechanisms through which NF-κB affects HSC functions. In specific aim 2, we will unravel the extrinsic role of NF-κB in the control of HSCs. In specific aim 3, we would generate a novel humanized mouse model and decode the involvement of NF-κB signals in human HSC biology. We believe that the proposed research will provide key insights into the pathologic processes involving deregulated NF-κB signals, and will aid the development of newer and more successful therapies for human hematologic diseases that arise due to constitutive NF-κB activation.

项目概要： NF-κB 信号通路是研究和理解最广泛的信号通路之一 然而，增强 NF-κB 信号传导的生理影响 造血作用尚未被了解。尽管最近许多研究记录 血液系统疾病（包括 AML）患者中 NF-κB 的组成型激活 和 MDS，目前尚不清楚组成型 NF-κB 信号传导是否足够和/或 疾病发生所必需的。最近，我们发现缺乏 A20（a 造血干细胞 (HSC) 中的 NF-κB 负调节因子会导致 由于 NF-κB 的持续激活，导致静止期和严重的血液学异常。 为了直接破译 NF-κB 在 HSC 中的作用，我们对小鼠进行了改造 持续激活 HSC 中的 NF-κB。我们的初步数据表明 HSC 静止和池完全消失，仅增加 NF-κB 信号 足以干扰 HSC 的转录调节回路。在提议的 研究，我们想解码潜在的分子机制 NF-κB 信号增加会影响 HSC 生物学。 我们的假设是，规范 NF-κB 信号失调会损害造血功能 干细胞 (HSC) 静止并通过改变信号转导发挥作用 通路、“转录因子网络”和促炎因子的表达 细胞因子。为了检验这个假设，我们将结合遗传、分子细胞 生物学和生化方法。在具体目标1中，我们将破译内在的 NF-κB 影响 HSC 功能的机制。在具体目标2中，我们将 揭示 NF-κB 在 HSC 控制中的外在作用。在具体目标 3 中，我们将 生成新型人源化小鼠模型并解码 NF-κB 的参与 人类 HSC 生物学中的信号。 我们相信，拟议的研究将为以下问题提供重要见解： 涉及失调 NF-κB 信号的病理过程，并将有助于发育 针对人类血液疾病的更新、更成功的疗法 NF-κB 的组成型激活。