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

芳香烃受体(AHR)是一种配体激活的转录因子，是全球性的环境因子 传感器对外源性和内源性微环境配体的反应起着中心作用 发挥协调造血干、祖细胞代谢状态的作用。做出的选择是 造血干细胞在保持静止和自我更新之间，而不是增殖和 分化为血统受限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。分解代谢的定义是细胞器和蛋白质的自我循环 更新和静止，而合成代谢产生的能量和营养物质推动增殖和 差异化。因此，推动这项研究和后续研究的根本问题是， AHR在造血过程中对分解代谢和合成代谢平衡的生理作用？ 我们团队的长期目标是揭示AHR调节细胞新陈代谢的机制 造血干细胞向效应免疫细胞转化过程中的状态 微环境刺激。为了追求我们的目标，这项高风险-高回报R21提案的目标是 确定AHR在造血干线粒体全局调控中的作用和谱系偏向 祖细胞。最重要的假设是，AHR是造血代谢的中心调节器。 和免疫系统的祖细胞。AHR是新陈代谢中枢调节因子的科学前提是 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 干细胞受AHR特异性调节；和(2)AHR是最大限度的氧化爆发所必需的。 造血祖细胞。用来询问总体假设的三个具体目的是：目的 1：确定造血过程中线粒体生物发生所需的AHR信号阈值。目标2： 确定AHR依赖信号在造血祖细胞合成代谢活性中的作用。目标3： 建立维持造血细胞分解代谢活性所需的AHR依赖的信号阈值 干细胞。这一建议意义重大，因为它将首次确定AHR在 分解代谢和合成代谢活动的平衡，从而调节HSC的新陈代谢和谱系偏向免疫 细胞祖细胞。这项提议极具创新性，因为它代表了对现状的实质性改变。 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， 增殖分化。这些研究的预期结果将是实时可视化 在造血干和祖细胞中，线粒体的动态平衡依赖于AHR的活性。积极的一面 这项拟议工作的影响将成为治疗代谢引起的血液病的新途径 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.