NF-kB signaling in the control of Hematopoiesis

项目摘要： 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。

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.