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信号通路是研究和理解最广泛的一种然而，途径，增强NF-κB信号在中的生理影响尽管最近有许多研究记录了造血作用。血液疾病患者的NF-κB的征服激活，倾斜AML 和MDS，它仍然是毫无意义的NF-κB信号，是选举权和或或或或或或或对于疾病的发作所必需的。 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，我们将小鼠设计为征兵激活HSC中的NF-κB。静止和池完全丢失，仅增加NF-κB信号是足以干扰提议中HSC的转录调节回路研究，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，牙本质的规范NF-κB信号受损造血症。干细胞（HSC）静止和功能通过改变信号转导途径，“转录因子网络”和促炎的表达细胞因子。为了检验这一假设，我们将使用遗传，分子细胞的组合生物学和生化方法。机理Thich NF-κB会影响特定目标的HSC功能。揭开NF-κB在特定目标中的控制中的外在作用。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，支撑研究将为您提供关键的见解涉及失调的NF-κB信号的病理过程，将有助于发展由于应得的新的，更成功的Heman血液学疾病疗法征服NF-κB激活。