T-cell Mediation of Focal Bone Loss Induced by Transient Muscle Paralysis

描述(由申请人提供)：本提案的主要目标是确定介导由一过性肌肉麻痹引起的局灶性骨丢失的细胞类型。具体地说，短暂性肌肉麻痹通过RANKL介导的过程迅速诱导局灶性破骨细胞介导的骨小梁和皮质骨丢失。此外，激活的T细胞已被证明通过类似的RANKL途径在急性骨丢失模型中介导局部破骨细胞的形成。这一建议将探索激活的T细胞介导由一过性肌肉麻痹引起的局灶性骨丢失的假说。为了探索这一普遍假设，工程学和生物技术(急性骨丢失的小鼠模型、体内高分辨率骨成像、图像配准和操作、流式细胞仪、基因和药物改变的小鼠以及免疫荧光成像)将被用于实现三个特定目标。这些目标将包括：1)确定胫骨近端干骺端骨小梁图像配准的分辨率；2)确定一过性肌肉麻痹后激活的T细胞是否显著上调；以及3)确定一过性肌肉瘫痪后激活的T细胞是否与胫骨近端干骺端骨吸收的起始点共存。这项研究结合了一种新的量化方法和一个快速诱导破骨细胞生成的模型，以评估一个可能的候选中介细胞，T细胞，是否在空间和时间上与最初发生骨吸收的部位有关。由于该模型提供了研究肌肉功能和骨骼内稳态之间相互作用的独特能力，这项研究的主要发现将对与年龄相关的肌肉质量退化(骨质疏松症)和类似年龄相关的骨量减少(骨质疏松症)之间的联系提供临床相关的见解。 公共卫生相关性：该项目的重点是通过实验确定一种候选细胞类型，该细胞类型可以调节由一过性肌肉麻痹引起的局灶性骨丢失。从临床角度来看，这项建议中的发现将为与衰老相关的骨量退化(骨质疏松症)和肌肉质量(骨质疏松症)之间的潜在因果关系提供相关的见解。

DESCRIPTION (provided by applicant): The broad goal of this proposal is to determine the cell type that mediates focal bone loss induced by transient muscle paralysis. Specifically, transient muscle paralysis rapidly induces focal osteoclast mediated trabecular and cortical bone loss though a RANKL mediated process. Additionally, activated T-cells have been shown to mediate focal osteoclastogenesis in models of acute bone loss through similar RANKL pathways. This proposal will explore the hypothesis that activated T-cells mediate focal bone loss induced by transient muscle paralysis. To explore this general hypothesis, an integrated approach combining engineering and biological techniques (murine model of acute bone loss, high-resolution in vivo bone imaging, image registration and manipulation, flow cytometry, genetically and pharmaceutically altered mice, and immunoflourescent imaging) will be used to pursue three Specific Aims. These Aims will include: 1) defining the resolution of proximal tibia metaphysis trabecular image registration, 2) determining if activate T-cells are acutely up-regulated following transient muscle paralysis, and 3) determining if activated T-cells are co-localized with the initiation sites of bone resorption in the proximal tibia metaphysis following induction of transient muscle paralysis. This fellowship combines a novel quantification approach with a model of rapidly induced osteoclastogenesis to assess whether a likely candidate mediator cell, T-cells, are spatially and temporally associated with sites where bone resorption first occurs. As this model provides the unique ability to study the interaction between muscle function and bone homeostasis, the primary findings in this fellowship will yield clinically relevant insights into the link between aging related degeneration of muscle mass (sarcopenia) and similar age related decreases in bone mass (osteoporosis). PUBLIC HEALTH RELEVANCE: This project is focused on experimentally identifying a candidate cell type that mediates focal bone loss induced by transient muscle paralysis. From a clinical perspective, the findings in this proposal would provide relevant insight into a potential causal relationship between aging related degeneration of bone mass (osteoporosis) and muscle mass (sarcopenia).