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

芳基烃受体对造血和免疫细胞祖细胞代谢的调节

• 批准号: 10538613
• 负责人: Michael D Laiosa
• 金额: $ 18.73万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538613
• 关键词: Acceleration; Adult; Agonist; Aryl Hydrocarbon Receptor; Automobile Driving; Biogenesis; Biological Assay; Catabolism; Cell Proliferation; Cells; Child; Confocal Microscopy; Data; Development; Dioxins; Disease; Environmental Exposure; Environmental Pollutants; Equilibrium; Exposure to; Flow Cytometry; Fluorescence; Foundations; Goals; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Immune; Immune System Diseases; Immune system; Immunocompromised Host; Individual; Label; Laboratories; Ligands; Link; Measures; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Mus; National Institute of Environmental Health Sciences; Nutrient; Organelles; Outcome; Outcome Study; Pathway interactions; Persons; Physiologic pulse; Physiological; Play; Population; Prevention strategy; Process; Production; Proliferating; Proteins; Public Health; Publishing; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Recycling; Regulation; Reporter; Respiratory Burst; Role; Signal Transduction; Stimulus; System; Testing; Tetrachlorodibenzodioxin; Time; United States; United States National Institutes of Health; Visualization; Work; antagonist; blood formation; design; global environment; high reward; high risk; innovation; leukemia; metabolomics; mitochondrial dysfunction; novel; progenitor system; response; self-renewal; sensor; stem; stem cells; transcription factor; treatment strategy

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.

芳基烃受体（AHR）是配体激活的转录因子和全球环境 我们建议的传感器对外源和内源性微环境配体有反应 角色协调造血茎和祖细胞的代谢状态。选择 造血干细胞之间持续静止与自我更新，相对于增殖和 区分谱系限制的祖细胞，基于促进分解代谢的信号平衡 与合成代谢的代谢活动相比。分解代谢是通过循环细胞器和蛋白质的自我来定义的 更新和静止 分化。因此，将推动这一点的基本问题，随后的研究是什么 AHR的生理作用在造血过程中分解代谢与合成代谢的平衡之间的平衡？ 我们团队的长期目标是发现AHR调整细胞代谢的机制 在从造血干细胞到效应免疫细胞的过渡期间的状态 微环境刺激。为了追求我们的目标，这种高风险的目标 - 高奖励R21提案是 确定AHR在造血茎和谱系偏置中的全球线粒体调节中的作用 祖细胞。总体假设是AHR是造血中代谢的中心调节剂 和免疫系统祖细胞。 AHR是代谢的中心调节者的科学前提是 部分地基于我们令人兴奋的初步数据，该数据显示：（1）造血的线粒体数量 干细胞由AHR特别调节。 （2）最大氧化爆发需要AHR 造血祖细胞。询问总体假设的三个特定目标是：目标 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2： 确定AHR依赖性信号对造血祖细胞合成代谢活性的贡献。目标3： 建立依赖AHR的信号传导阈值，以维持造血的分解代谢活动 干细胞。该提议很重要，因为它将首次确定AHR的身体角色 分解代谢与合成代谢活动的平衡，从而控制HSC的代谢和谱系偏见的免疫 细胞祖细胞。该提议具有很高的创新性，因为它代表了与现状的实质性不同 通过将AHR造血调节的机理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 线粒体稳态取决于造血茎和祖细胞中的AHR活性。积极 拟议工作的影响将是治疗由代谢引起的血液学疾病的新途径 和线粒体功能障碍。