PERIPHERAL NERVE DISTRIBUTION AND FUNCTION WITHIN THE SKELETON

骨骼内周围神经的分布和功能

• 批准号: 9768475
• 负责人: Erica Lynn Scheller
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 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/9768475
• 关键词: Acute; Adipocytes; Afferent Neurons; Architecture; Bone Marrow; Bone Regeneration; Cells; Chronic; Classification; Clinical; Data; Diabetes Mellitus; Disease; Elderly; Equilibrium; Fracture; Functional disorder; Future; Goals; Health; Hematopoietic; Homeostasis; Human; Impairment; Knowledge; Laboratories; Lead; Literature; Maintenance; Mus; Natural regeneration; Nerve; Neuroanatomy; Neurobiology; Neurotransmitters; Norepinephrine; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Outcome; Patients; Peripheral; Peripheral Nerve Stimulation; Peripheral Nerves; Phenotype; Population; Presynaptic Terminals; Prevention; Quality of life; Rattus; Reflex action; Regulation; Research; Risk; Rodent; Schwann Cells; Sensory; Signal Transduction; Site; Skeleton; Spinal Ganglia; Stimulus; Structure of trigeminal ganglion; Techniques; United States; Viral; Work; afferent nerve; base; bioelectricity; bone; bone disuse atrophy; bone loss; density; fracture risk; high risk population; insight; mortality; nerve supply; neurotransmission; neurotransmitter release; novel; prevent; response; side effect; skeletal; skeletal regeneration; skeletal tissue; spinal nerve posterior root

PROJECT SUMMARY Our long-term goal is to understand the function of nerves within bone, how changes to skeletal innervation with disease impact bone pathophysiology, and whether bioelectric stimulation can be used to promote skeletal health and bone accrual. Despite decades of research, there is only one clinical anabolic therapy to treat patients with bone loss and elevated fracture risk - and its use is limited to a total of only 2-years during a patient’s lifetime. Bioelectric stimulation of nerve outflow to skeletal tissues represents a novel, untapped option with significant clinical potential. Current literature supports a paradigm by which sensory neurotransmitters are anabolic, promoting bone formation, while the sympathetic neurotransmitter norepinephrine induces bone loss. Thus, selective activation of sensory nerve depolarization and release of efferent neurotransmitters may promote bone formation and contribute to decreased skeletal fragility in high- risk populations. A substantial barrier to taking such a targeted approach is our limited understanding of nerve distribution and function within the bone and bone marrow. To overcome this, the work in this proposal will establish critical fundamental insights into three key aspects of skeletal neurobiology. In Aim 1, we will define the connection and overlap of multiple, diverse skeletal regions across the central neuroaxis, including sub- classification of traced first-order sensory neurons in the dorsal root and trigeminal ganglia. In Aim 2, we will quantify the distribution and density of sensory and sympathetic nerves within the bone and bone marrow, and its variability across skeletal sites in mice and humans. This analysis will be paired with characterization of functional secondary architecture including the presence of Schwann cells around skeletal axons and terminal target relations with bone-forming osteoblasts, bone-resorbing osteoclasts, and hematopoietic cells. In Aim 3, we will directly examine the impact of bioelectric stimulation on bone and bone marrow including acute changes in soluble signaling factors and chronic regulation of skeletal health and integrity. The fundamental knowledge developed from the work in this proposal will provide essential information about the distribution and function of skeletal nerves to the SPARC consortium and inform future targeted approaches for bioelectric stimulation of skeletal health and regeneration.

项目摘要 我们的长期目标是了解骨骼内神经的功能，如何变为骨骼神经 疾病影响骨骼病理生理学，以及是否可以使用生物电刺激来促进骨骼 健康和骨骼。尽管进行了数十年的研究，但只有一种临床合成代谢疗法可以治疗 骨质流失和骨折风险升高的患者 - 在A期间，其使用量仅限于2年 病人的一生。对骨骼组织的神经出口的生物电刺激代表了一种新颖的，未开发的 具有巨大临床潜力的选项。当前文献支持一种范式 神经递质是合成代谢的，促进了骨形成，而交感神经递质 去甲肾上腺素会诱导骨质流失。这是感觉神经去极化和释放的选择性激活 传出的神经递质可能会促进骨骼形成，并导致骨骼脆弱性降低 风险人群。采用这种有针对性的方法的一个实质性障碍是我们对神经的理解有限 骨髓和骨髓内的分布和功能。为了克服这一点，该提议中的工作将 对骨骼神经生物学的三个关键方面建立关键的基本见解。在AIM 1中，我们将定义 中央神经障碍的多个多元化骨骼区域的连接和重叠，包括亚 在背根和三叉神经节中追踪的一阶感觉神经元的分类。在AIM 2中，我们将 量化骨和骨髓内的感觉和交感神经的分布和密度，以及 它在小鼠和人类的骨骼部位之间的变异性。该分析将与 功能性二级结构，包括骨骼轴突周围和末端周围的雪旺单元的存在 靶向与骨形成骨细胞，骨呈现骨细胞和造血细胞的关系。在AIM 3中， 我们将直接检查生物电刺激对骨髓和骨髓的影响 固体信号因子的变化和骨骼健康和完整性的慢性调节。基本 该提案中的工作中开发的知识将提供有关分配的基本信息 骨骼神经对SPARC财团的功能，并告知未来的目标方法 刺激骨骼健康和再生。

项目成果

MarrowQuant Across Aging and Aplasia: A Digital Pathology Workflow for Quantification of Bone Marrow Compartments in Histological Sections.

• DOI: 10.3389/fendo.2020.00480
• 发表时间: 2020
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Tratwal J;Bekri D;Boussema C;Sarkis R;Kunz N;Koliqi T;Rojas-Sutterlin S;Schyrr F;Tavakol DN;Campos V;Scheller EL;Sarro R;Bárcena C;Bisig B;Nardi V;de Leval L;Burri O;Naveiras O
• 通讯作者: Naveiras O

Neural regulation of bone marrow adipose tissue.

• DOI: 10.1016/j.beem.2021.101522
• 发表时间: 2021-07
• 期刊: Best practice & research. Clinical endocrinology & metabolism
• 作者: Zhang X;Hassan MG;Scheller EL
• 通讯作者: Scheller EL