NF-kB signaling in the control of Hematopoiesis

NF-kB 信号传导在造血控制中的作用

基本信息

批准号：
10087951
负责人：
Chozha Vendan Rathinam
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10087951
关键词：
AML/MDS 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 Cytokine Receptors Data Development Disease Dysmyelopoietic Syndromes Engineering Equilibrium Gene Expression Profiling Genetic Genetic Transcription Hematologic Neoplasms Hematological Disease Hematology 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 TNF gene Techniques Testing Transplantation Work Xenograft Model base chromatin immunoprecipitation cytokine exhaustion gain of function hematopoietic stem cell quiescence hematopoietic stem cell self-renewal high risk human disease humanized mouse in silico innovation insight leukemia treatment mouse model novel physiologic stressor premature prevent public health relevance response stem cell biology stem cell function stem cells transcription factor transcriptome

项目摘要

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。