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. !

项目总结： 骨髓是造血的主要场所，所有的血细胞都是从这里出来的。 造血干细胞(HSCs)的调节分化。研究来自于 申请人的实验室发现了交感神经支配的关键功能 造血干细胞出骨髓的神经系统(SNS)。SNS神经被要求 包括HSCs的昼夜释放和成熟的昼夜募集 白血球外周。此外，骨髓也受到肽能神经的支配。 感觉纤维在造血中的作用尚不清楚。在此应用程序中，我们 提出一项为期3年的试验计划，以增进我们对 骨髓的神经解剖学和神经生理学。在具体目标1中，我们将 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束追踪的神经回路， 并评估感觉纤维和三叉神经纤维之间的信号相互作用 药理和遗传模型系统。在具体目标2中，我们将确定 在骨髓中传递SNS神经信号的细胞间转导通路。我们会 识别接收介导ROS振荡的肾上腺素能信号的基质细胞类型 这可能是神经信号传播的重要环节。特定目标 3利用内源性神经回路促进造血再生。我们会 用腺病毒转导建立选择性骨髓DREADDS 器官特异性神经激活以促进遗传毒性侮辱后的再生 例如电离辐射或化疗。内源性神经回路的操作 可能确实提供了一种有用的未来加速造血再生的策略。 好了！