Neuronal Modulation of Focal Bone Homeostasis

焦点骨稳态的神经元调节

• 批准号: 8022205
• 负责人: TED S. GROSS
• 金额: $ 34.85万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022205
• 关键词: Neuronal; Modulation; Focal; Bone; Homeostasis

DESCRIPTION (provided by applicant): In part to explore the specific signaling pathways that underlie the co-dependency between muscle and bone, we have developed a novel in vivo murine model of transient muscle paralysis that inhibits both motor and sensory signaling following intramuscular injections of botulinum toxin A (BTxA). Despite a mild and transient gait deficit, we have shown that the loss of trabecular bone following transient muscle paralysis is rapid and profound and dominated by RANKL mediated osteoclastic resorption. Our preliminary data with a mouse hindlimb specific defect in proprioception has led us to hypothesize that trabecular bone homeostasis is modulated by neuromuscular proprioception. In this project we will pursue this thesis through four closely related sub-hypotheses each with a corresponding Specific Aim. The first three S. Aims seek to demonstrate that while mechanical stimuli clearly influence trabecular bone homeostasis, muscle proprioception plays a previously unrecognized, but fundamental role in modulating local trabecular bone morphology. In the final S. Aim we will attempt to clarify that a neuronally mediated inflammatory response precedes and mediates the profound osteoclastic resorption acutely induced by transient muscle paralysis. If these data support our hypothesis, we believe that our results hold potential to alter current approaches to intervene or prevent bone loss in a variety of musculoskeletal pathologies. PUBLIC HEALTH RELEVANCE: This project seeks to elucidate a fundamental, but as yet unrecognized neuronal pathway by which normal trabecular bone homeostasis is achieved and maintained. From a clinical perspective, we believe that understanding the role that sensory proprioception plays in modulating local trabecular bone homeostasis will directly enable novel interventions into both acute (e.g., spinal cord injury, general disuse) and chronic (e.g., associated with aging) bone loss pathologies.

描述（由申请人提供）：为了探索肌肉和骨骼之间相互依赖的特定信号通路，我们开发了一种新的小鼠体内短暂性肌肉麻痹模型，该模型在肌肉注射肉毒杆菌毒素a （BTxA）后抑制运动和感觉信号。尽管有轻微和短暂的步态缺陷，但我们已经表明，短暂性肌肉麻痹后小梁骨的损失是迅速而深刻的，主要是RANKL介导的破骨细胞吸收。我们对小鼠后肢本体感觉特异性缺陷的初步数据使我们假设小梁骨稳态是由神经肌肉本体感觉调节的。在这个项目中，我们将通过四个密切相关的子假设来追求这篇论文，每个子假设都有相应的具体目标。前三个S. Aims试图证明，虽然机械刺激明显影响小梁骨稳态，但肌肉本体感觉在调节局部小梁骨形态方面起着以前未被认识到的基础性作用。在最后的S. Aim中，我们将试图阐明神经介导的炎症反应先于并介导由短暂性肌肉麻痹急性诱导的深度破骨细胞吸收。如果这些数据支持我们的假设，我们相信我们的结果有可能改变目前干预或预防各种肌肉骨骼病理骨质流失的方法。