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

项目总结/摘要 随着年龄的增长而发生的运动功能的丧失与不利的健康状况密切相关 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（NMJ）的变性，α-运动神经之间形成的突触 神经元和骨骼肌纤维，有助于与年龄相关的运动功能障碍。作为最终 作为躯体运动系统的输出，NMJ的退化不可避免地导致退化 运动神经轴突和肌肉纤维萎缩，从而影响自主运动。照经上所 关键是要确定的因素，功能，以维持和修复NMJ。使用R56赠款 由NIA提供，我们实验室已经鉴定了成纤维细胞生长因子结合蛋白1（FGFBP 1）， 作为一个有前途的候选因子分泌的肌肉纤维，以保持和恢复的完整性 在衰老过程中FGFBP 1的功能是从细胞外的FGF配体伴侣 matrix基质to cognate同源receptor受体.以这种方式，它增强FGF信号传导。我们发现 虽然FGFBP 1在年轻成年小鼠中集中在NMJ，但它在发育过程中逐渐减少。 在正常衰老和SOD 1G 93 A小鼠中，ALS的小鼠模型。使用基因敲除小鼠，我们 观察到FGFBP 1的表达是减缓NMJ衰老和运动缺陷所必需的。 正常老化。此外，表达SOD 1G 93 A的小鼠中FGFBP 1缺失， 肌萎缩侧索硬化症（ALS）加速NMJ变性、疾病进展和 死亡这些初步的发现有力地表明，防止内源性 FGFBP 1在衰老过程中可能足以减缓NMJ的退化，从而保护运动神经元。 功能为了验证这一假设，我们提出了三个相互依存的具体目标。在 目的1，我们检验了FGFBP 1缺陷小鼠的运动缺陷是由以下原因引起的假设： NMJ的细胞、分子和生理变化。在目标2中，我们将寻求确定 在衰老肌肉中抑制FGFBP 1表达的分子机制。在目标3中，我们将测试 FGFBP 1足以预防和逆转NMJ的年龄相关变化的假设。 这些目标旨在揭示促使纳米材料老化的初始变化， 导致衰老肌肉中FGFBP 1表达降低的分子因子， FGFBP 1在保护NMJ和运动功能方面的治疗潜力。

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.