NF-kB signaling in the control of Hematopoiesis

项目总结： 核因子-κB信号通路是目前研究和理解最广泛的信号通路之一 然而，通路中，增强的NF-κB信号的生理影响 造血功能还不是很清楚。尽管最近的许多研究记录了 包括急性髓系白血病在内的血液病患者核因子-κB的结构性激活 和MDS，目前尚不清楚结构性的NF-κB信号是否足够和/或 对于疾病的发病来说是必要的。最近，我们发现缺乏A20(a 造血干细胞(HSCs)中的核因子-κB负性调节因子)导致 静止和严重的血液学异常，由结构性的NF-κB激活所致。 为了直接破译核因子-κB在造血干细胞中的作用，我们让小鼠 结构性激活HSCs中的NF-κB。我们的初步数据表明，HSC 静息和池完全消失，单独增加的NF-κB信号是 足以干扰肝星状细胞的转录调控电路。在建议的 研究，我们想破译潜在的分子机制，通过它 升高的核因子-κB信号影响造血干细胞的生物学。 我们的假设是，去调节的规范的NF-κB信号损害了造血 干细胞(HSC)在改变信号转导中的静息和功能 途径、“转录因子网络”与促炎因子的表达 细胞因子。为了验证这一假设，我们将使用遗传、分子细胞的组合 生物学和生化方法。在具体目标1中，我们将破译 核因子-κB影响造血干细胞功能的机制。在具体目标2中，我们将 揭示核因子-κB在造血干细胞调控中的外在作用。在具体目标3中，我们将 一种新型人源化小鼠模型的建立及对NF-κB参与的解码 人类HSC生物学中的信号。 我们相信，拟议的研究将为 涉及去调节的NF-κB信号的病理过程，并将有助于发展 针对人类血液病的更新、更成功的治疗方法 与组成性的核因子-κB激活有关。

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.