Targeting the fibroblast growth factor binding protein-1 to slow degeneration of neuromuscular junctions

项目摘要/摘要 随着年龄增长而出现的运动功能丧失与健康不良密切相关。 结果。近年来，发表的研究结果强烈表明，故障和 神经肌肉接头退行性变，α-运动之间形成的突触 神经元和骨骼肌纤维，导致与年龄相关的运动功能障碍。作为决赛 躯体运动系统的输出，NMJ的退变必然导致退变 运动轴突变性和肌肉纤维萎缩，从而影响自主运动。因此，它是 确定维持和修复NMJ的关键因素。使用R56拨款 由NIA提供，本实验室已鉴定出成纤维细胞生长因子结合蛋白1(FGFBP1) 作为一种有希望的候选因子，由肌肉纤维分泌，以保持和恢复完整性 在老化过程中的NMJ。FGFBP1对来自细胞外的伴侣成纤维细胞生长因子配体的作用 从母体到同源受体。通过这种方式，它增强了成纤维细胞生长因子信号。我们发现， 虽然FGFBP1在幼年小鼠的NMJ处集中，但在 正常衰老，在SOD1G93A小鼠中，建立ALS小鼠模型。使用基因敲除的小鼠，我们 观察到FGFBP1的表达是减缓NMJ衰老和运动障碍所必需的 正常衰老。此外，在表达SOD1G93A的小鼠中，FGFBP1缺失，一种 肌萎缩侧索硬化症(ALS)，加速NMJ变性，疾病进展和 死亡。这些初步发现有力地表明，防止内源性营养物质的损失 FGFBP1在衰老过程中可能足以减缓NMJ的退变，从而保护运动 功能。为了检验这一假设，我们提出了三个相互建立的具体目标。在……里面 目的1，我们验证了FGFBP1缺陷小鼠的运动缺陷是由 NMJ的细胞、分子和生理变化。在目标2中，我们将努力确定 抑制衰老肌肉中FGFBP1表达的分子机制。在目标3中，我们将测试 假设FGFBP1足以预防和逆转NMJ的年龄相关性变化。 这些目标旨在揭示加速NMS老化的初始变化，即 导致衰老肌肉中FGFBP1表达降低的分子因素，以及 FGFBP1对保护NMJ和运动功能的治疗潜力。

Project Summary/Abstract The loss of motor function that occurs with aging is closely associated with adverse health outcomes. In recent years, published findings strongly suggest that malfunction and degeneration of the neuromuscular junction (NMJ), the synapse formed between α-motor neurons and skeletal muscle fibers, contributes to age-related motor dysfunction. As the final output of the somatic motor system, degeneration of the NMJ inevitably results in degeneration of motor axons and atrophy of muscle fibers, thus affecting voluntary movement. Thus, it is critical to identify factors that function to maintain and repair the NMJ. Using an R56 grant provided by NIA, our lab has identified the fibroblast growth factor binding protein 1 (FGFBP1) as a promising candidate factor secreted by muscle fibers to preserve and restore the integrity of NMJs during aging. FGFBP1 functions to chaperone FGF ligands from the extracellular matrix to cognate receptors. In this manner, it enhances FGF signaling. We have found that while FGFBP1 concentrates at NMJs in young adult mice, it progressively decreases during normal aging and in SOD1G93A mice, a mouse model for ALS. Using knockout mice, we observed that FGFBP1 expression is required to slow aging of NMJs and motor deficits during normal aging. Furthermore, FGFBP1 deletion in mice expressing SOD1G93A, a model for amyotrophic lateral sclerosis (ALS), accelerates NMJ degeneration, disease progression and death. These initial discoveries strongly suggest that preventing loss of endogenous of FGFBP1 during aging may be sufficient to slow degeneration of NMJs, and thus preserve motor function. To test this hypothesis, we proposed three specific aims that build on each other. In aim 1, we test the hypothesis that motor deficits in mice deficient for FGFBP1 result from cellular, molecular, and physiological changes at NMJs. In aim 2, we will seek to identify molecular mechanisms that inhibit FGFBP1 expression in aging muscles. In aim 3, we will test the hypothesis that FGFBP1 is sufficient to prevent and reverse age-related changes of NMJs. These aims are designed to uncover the initial changes that precipitate aging of NMs, the molecular factors that result in decreased FGFBP1 expression in aging muscle, and the therapeutic potential of FGFBP1 in preserving NMJs and motor function.