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.

项目摘要： NF-κB信号通路是最广泛的研究途径之一，并理解 但是，途径，增强NF-κB信号传导的物理影响 尚未理解造血。尽管最近有许多研究记录了 血液学疾病患者（包括AML）的NF-κB的组成型激活 和MDS，目前尚不清楚配置NF-κB信号是否足够和/或 疾病发作所必需的。最近，我们表明缺乏A20（a NF-κB的负调节剂）在造血干细胞（HSC）中导致丧失 由于组成型NF-κB激活，静止和严重的血液学异常。 为了使NF-κB在HSC中的作用中解密，我们将小鼠设计为 组成性激活HSC中的NF-κB。我们的初步数据表明HSC 静止和池完全丢失，仅增加NF-κB信号是 足以干扰HSC的转录调节回路。在提议中 研究，我们想解码潜在的分子机制 NF-κB信号的增加会影响HSC生物学。 我们的假设是，放松管制的规范NF-κB信号会损害造血 干细胞（HSC）静止和通过改变信号转导的功能 途径，“转录因子网络”和促炎的表达 细胞因子。为了检验该假设，我们将使用遗传，分子细胞的组合 生物学和生化方法。在特定的目标1中，我们将破译固有的 NF-κB影响HSC功能的机制。在特定的目标2中，我们将 揭示NF-κB在控制HSC中的外在作用。在特定的目标3中，我们会 生成一种新型的人性化小鼠模型并解码NF-κB的参与 人类HSC生物学中的信号。 我们认为，拟议的研究将为您提供关键的见解 病理过程涉及放大NF-κB信号，并将有助于发展 应得的新的，更成功的人类血液学疾病疗法 组织NF-κB激活。