Evaluating neural circuitry of the bone marrow

评估骨髓的神经回路

• 批准号: 9768488
• 负责人: Paul S Frenette
• 金额: $ 41.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768488
• 关键词: Adrenergic Agents; Amplifiers; Biological Models; Blood; Blood Cells; Bone Marrow; Bone Marrow Ablation; Cell Adhesion Molecules; Cell Count; Cell Maintenance; Cells; Data; Dependovirus; Diphtheria Toxin; Discontinuous Capillary; Drug usage; Endothelial Cells; Fiber; Future; Genetic Models; Genetically Engineered Mouse; Genotoxic Stress; Growth Factor; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Image; Immunofluorescence Immunologic; In Vitro; Ions; Knowledge; Laboratories; Lead; Leukocytes; Link; Location; Maps; Marrow; Mediating; Natural regeneration; Nerve; Nerve Fibers; Neuroanatomy; Neurons; Organ; Pathway interactions; Pharmacology; Phenotype; Reactive Oxygen Species; Receptor Signaling; Reproducibility; Role; Sensory; Signal Transduction; Site; Stromal Cells; Sympathetic Nervous System; Technology; Therapeutic; Tissues; Viral; afferent nerve; arteriole; base; beta-adrenergic receptor; biological adaptation to stress; cell type; chemotherapy; circadian; cytokine; designer receptors exclusively activated by designer drugs; genotoxicity; hematopoietic differentiation; improved; irradiation; mesenchymal stromal cell; model development; nerve supply; neural circuit; neural growth; neural stimulation; neurophysiology; neuroregulation; neurotransmission; novel strategies; overexpression; recruit; relating to nervous system; response; transmission process

PROJECT SUMMARY: The bone marrow is the major site of hematopoiesis where all blood cells emerge from the regulated differentiation of hematopoietic stem cells (HSCs). Studies from the applicant’s laboratory have uncovered key functions for innervation of the sympathetic nervous system (SNS) in the egress of HSCs from marrow. SNS nerves are required to entrain the circadian release of HSCs and also the circadian recruitment of mature leukocytes to the periphery. In addition, the bone marrow is also innervated by peptidergic sensory fibers whose functions in hematopoiesis remain unclear. In this application, we propose a 3-year experimental plan that will advance our knowledge on the neuroanatomy and neurophysiology of the bone marrow. In Specific Aim 1, we will characterize the functions of sensory nerves in the marrow. We will define the functional neural circuits using immunofluorescence imaging and transneuronal viral tract tracing, and evaluate the interplay of signals between sensory and SNS fibers using pharmacological and genetic model systems. In Specific Aim 2, we will identify the intercellular transduction pathways that relay SNS nerve signals in bone marrow. We will identify the stromal cell types that receive adrenergic signals mediating ROS oscillations which may represent an important link for the propagation of neural signals. Specific Aim 3 will harness endogenous neural circuits to improve hematopoietic regeneration. We will establish selective bone marrow DREADDs using adenoviral transduction that will lead to organ-specific neural activation to enhance regeneration following genotoxic insults such as ionizing irradiation or chemotherapy. Manipulation of endogenous neural circuits may indeed provide a useful future strategy to accelerate hematopoietic regeneration. !

项目概要： 骨髓是造血的主要部位，所有血细胞都从这里产生 造血干细胞 (HSC) 的调节分化研究。 申请人的实验室发现了交感神经支配的关键功能 造血干细胞从骨髓中排出时需要神经系统（SNS）。 促进 HSC 的昼夜释放以及成熟细胞的昼夜招募 此外，骨髓也受肽能神经支配。 感觉纤维在造血中的功能仍不清楚。 提出一个为期 3 年的实验计划，以增进我们对 在具体目标 1 中，我们将进行骨髓的神经解剖学和神经生理学。 描述骨髓中感觉神经的功能，我们将定义功能。 使用免疫荧光成像和跨神经元病毒道追踪的神经回路， 并使用以下方法评估感觉纤维和 SNS 纤维之间信号的相互作用 在具体目标 2 中，我们将确定药理学和遗传模型系统。 在骨髓中传递 SNS 神经信号的细胞间转导途径。 识别接收介导 ROS 振荡的肾上腺素信号的基质细胞类型 这可能代表了神经信号传播的重要环节。 3 将利用内源性神经回路来改善造血再生。 使用腺病毒转导建立选择性骨髓 DREADD，这将导致 器官特异性神经激活以增强基因毒性损伤后的再生 例如内源性神经回路的电离辐射或化疗。 确实可能为加速造血再生提供有用的未来策略。 ！