Regulation of metabolism by the Aryl hydrocarbon receptor in hematopoietic and immune cell progenitors

芳香烃受体（aryl hydrocarbon receptor，AHR）是一种配体激活的转录因子， 传感器响应外源性和内源性微环境配体，我们建议发挥核心作用 协调造血干细胞和祖细胞代谢状态的作用。作出的选择 造血干细胞在保持静止和进行自我更新之间，相对于增殖和 分化为谱系限制的祖细胞，是基于促进分解代谢的信号平衡。 与合成代谢活动的对比。细胞器的定义是细胞器和蛋白质的再循环， 更新和静止，而能量和营养物质的合成代谢生产驱动增殖， 分化因此，推动这项研究和后续研究的根本问题是， AHR对造血过程中分解代谢与合成代谢平衡的生理作用？ 我们团队的长期目标是揭示AHR调节细胞代谢的机制， 在从造血干细胞到效应免疫细胞的转变过程中， 微环境刺激为了达到我们的目标，这项高风险高回报的R21建议的目的是 确定AHR在造血干细胞线粒体全局调节中的作用， 祖细胞总体假设是AHR是造血细胞代谢的中心调节因子， 和免疫系统祖细胞。AHR是代谢的中央调节器的科学前提是 部分基于我们令人兴奋的初步数据，这些数据显示：（1）造血细胞中线粒体的数量 干细胞由AHR特异性调节;（2）AHR是干细胞中最大氧化爆发所必需的。 造血祖细胞用于询问总体假设的三个具体目标是： 1：确定造血过程中线粒体生物发生所需的AHR信号传导阈值。目标二： 鉴定AHR依赖性信号传导对造血祖细胞合成代谢活性的贡献。目标3： 建立维持造血细胞分解代谢活性所需的AHR依赖性信号传导阈值 干细胞这一提议意义重大，因为它将首次确定AHR在以下方面的生理作用： 分解代谢与合成代谢活动的平衡，从而调节HSC的代谢和谱系偏向性免疫 细胞祖细胞这一建议具有高度创新性，因为它从实质上改变了现状 通过将AHR的造血调节机制与静止的代谢驱动因素联系起来， 增殖和分化。这些研究的预期结果将是实时可视化 造血干细胞和祖细胞中线粒体稳态依赖于AHR活性。的积极 所提出的工作的影响将是新的途径，用于治疗血液疾病引起的代谢 和线粒体功能障碍。

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and global environmental sensor responsive to exogenous and endogenous microenvironmental ligands that we propose plays a central role coordinating the metabolic state of hematopoietic stem and progenitor cells. The choice made by hematopoietic stem cells between remaining quiescent and undergoing self-renewal, versus proliferating and differentiating into a lineage-restricted progenitor cell, is based on the balance of signals that promote catabolic versus anabolic metabolic activities. Catabolism is defined by recycling of organelles and proteins for self- renewal and quiescence, whereas anabolic production of energy and nutrients drives proliferation and differentiation. Hence, the fundamental question that will drive this and subsequent studies is what is the physiological role for the AHR on the balance of catabolic versus anabolic metabolism during hematopoiesis? The Long-term goal of our team is to uncover the mechanisms by which the AHR tunes the cellular metabolic state during the transition from hematopoietic stem cell to effector immune cell in response to microenvironmental stimuli. In pursuit of our goal, the objective of this high risk – high reward R21 proposal is to identify the role for the AHR on global regulation of mitochondria in hematopoietic stem and lineage-biased progenitor cells. The overarching hypothesis is that the AHR is a central regulator of metabolism in hematopoietic and immune system progenitors. The scientific premise that the AHR is a central regulator of metabolism is grounded, in part, on our exciting preliminary data that show: (1) the number of mitochondria in hematopoietic stem cells is specifically regulated by the AHR; and (2) the AHR is required for maximal oxidative burst in hematopoietic progenitors. The three specific aims employed to interrogate the overarching hypothesis are: Aim 1: Determine the AHR signaling thresholds required for mitochondria biogenesis during hematopoiesis. Aim 2: Identify the contribution of AHR-dependent signaling on anabolic activity of hematopoietic progenitors. Aim 3: Establish the AHR-dependent signaling thresholds required for maintaining catabolic activities in hematopoietic stem cells. This proposal is significant because it will for the first time identify a physiological role for the AHR in the balance of catabolic vs anabolic activities, thereby regulating metabolism of HSC and lineage-biased immune cell progenitors. This proposal is highly innovative as it represents a substantive departure from the status quo by linking the mechanism of hematopoietic regulation by the AHR to the metabolic drivers of quiescence, proliferation and differentiation. An expected outcome from these studies will be real-time visualization of mitochondria homeostasis dependent on AHR activity in hematopoietic stem and progenitor cells. The positive impact of the proposed work will be new avenues for treatment of hematological diseases caused by metabolic and mitochondrial dysfunction.