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

描述（由申请人提供）：本提案的总体目标是确定介导短暂性肌肉麻痹引起的局局性骨丢失的细胞类型。具体来说，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，活化的t细胞已被证明通过类似的RANKL途径介导急性骨质流失模型中的局灶性破骨细胞发生。本研究将探讨激活的t细胞介导短暂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，将采用工程和生物技术相结合的综合方法（小鼠急性骨丢失模型，高分辨率体内骨成像，图像配准和操作，流式细胞术，遗传和药物修饰小鼠以及免疫荧光成像）来实现三个特定目标。这些目标将包括：1)确定胫骨近端干骺端小梁图像配准的分辨率，2)确定激活的t细胞是否在短暂性肌肉麻痹后急剧上调，以及3)确定激活的t细胞是否与诱发短暂性肌肉麻痹后胫骨近端干骺端骨吸收的起始位点共定位。本研究将一种新的定量方法与快速诱导破骨细胞发生模型相结合，以评估可能的候选中介细胞t细胞是否在空间和时间上与骨吸收首次发生的部位相关。由于该模型提供了研究肌肉功能和骨稳态之间相互作用的独特能力，因此本研究的主要发现将为与衰老相关的肌肉量退化（肌肉减少症）和与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。

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).