PERIPHERAL NERVE DISTRIBUTION AND FUNCTION WITHIN THE SKELETON

项目摘要 我们的长期目标是了解骨骼内神经的功能， 与疾病影响骨病理生理，以及生物电刺激是否可以用于促进骨骼 健康和骨骼增长。尽管几十年的研究，只有一个临床合成代谢治疗， 骨丢失和骨折风险升高的患者-并且其使用仅限于2年， 病人的一生生物电刺激神经流出骨骼组织代表了一种新的，未开发的 具有重大临床潜力的选择。当前的文献支持一种范式， 神经递质是合成代谢的，促进骨形成，而交感神经递质 去甲肾上腺素会导致骨质流失因此，选择性激活感觉神经去极化和释放 传出神经递质可能促进骨形成，并有助于降低骨骼脆性，在高- 风险人群。采取这种有针对性的方法的一个实质性障碍是我们对神经的有限理解 在骨骼和骨髓中的分布和功能。为了克服这一点，本提案中的工作将 对骨骼神经生物学的三个关键方面建立关键的基本见解。在目标1中，我们定义 跨中枢神经轴的多个不同骨骼区域的连接和重叠，包括亚 背根和三叉神经节中示踪的一级感觉神经元的分类。在目标2中，我们将 量化感觉神经和交感神经在骨和骨髓内的分布和密度，以及 它在小鼠和人类骨骼部位的变异性。该分析将与以下特征配对： 功能性二级结构，包括骨骼轴突周围的雪旺细胞和终末 与骨形成成骨细胞、骨吸收破骨细胞和造血细胞的靶向关系。在目标3中， 我们将直接检查生物电刺激对骨骼和骨髓的影响，包括急性 可溶性信号因子的变化和骨骼健康和完整性的慢性调节。根本 从本建议书的工作中获得的知识将提供有关分布的基本信息 和骨骼神经的功能，并为未来的生物电靶向方法提供信息。 刺激骨骼健康和再生。

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.