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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.

项目概要： NF-κB信号通路是目前研究最多的信号通路之一然而，增加NF-κB信号通路的生理影响，造血作用还不清楚。尽管最近的许多研究记录了包括AML在内的血液系统疾病患者中NF-κB的组成性激活和MDS，目前尚不清楚组成型NF-κB信号传导是否足够和/或是疾病发作所必需的。最近，我们已经表明，缺乏A20（a 造血干细胞（HSC）中NF-κB的负调节因子）导致造血干细胞（HSC）中NF-κB的缺失。静止和严重的血液学异常，由于组成性NF-κB活化。为了直接解读NF-κB在HSC中的作用，我们设计小鼠，组成性激活HSC中的NF-κB。我们的初步数据表明，HSC 静止和汇集完全丧失，单独增加NF-κB信号，足以干扰HSC的转录调节回路。拟议研究，我们想解码潜在的分子机制，增加的NF-κB信号影响HSC生物学。我们的假设是经典NF-κB信号失调损害造血功能，干细胞（HSC）通过改变信号转导的静止和功能通路、“转录因子网络”和促炎因子的表达细胞因子为了验证这一假设，我们将使用基因，分子细胞，生物学和生物化学方法。在具体目标1中，我们将破译 NF-κB影响HSC功能的机制。具体目标2：阐明NF-κB在HSC调控中的外在作用。具体目标3：构建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，拟议的研究将提供关键的见解，病理过程涉及NF-κB信号失调，并将有助于发展人类血液病的更新和更成功的疗法，组成性NF-κB激活。