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

靶向成纤维细胞生长因子结合蛋白-1 减缓神经肌肉接头的退化

基本信息

批准号：
9903183
负责人：
Gregorio Valdez
金额：
$ 32.69万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903183
关键词：
Affect Age Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Axon Brain Brain Diseases Caring Cessation of life Data Development Disease Disease Progression Epigenetic Process Extracellular Matrix FGFBP1 gene Fibroblast Growth Factor Goals Grant Health In Vitro Knock-out Knockout Mice Knowledge Length Ligands Measures Medical Mitochondria Modeling Modification Molecular Molecular Chaperones Motor Motor Neurons Movement Mus Muscle Muscle Fibers Muscular Atrophy Natural regeneration Neuromuscular Junction Outcome Output Pathway interactions Physiological Play Proteins Publishing Quality of life Recombinant Fibroblast Growth Factor Resources Role Schwann Cells Signal Transduction Skeletal Muscle Structure Subcellular structure Synapses Synaptic Vesicles System Testing Therapeutic Transforming Growth Factors Western Blotting Work age related base cholinergic cost design experimental study extracellular in vivo loss of function middle age motor deficit motor disorder mouse model muscle aging muscle degeneration normal aging premature preservation prevent quantum receptor repaired tool transcription factor transmission process young adult

项目摘要

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.

项目概要/摘要随着衰老而发生的运动功能丧失与不良健康密切相关近年来，发表的研究结果强烈表明，故障和神经肌肉接头（NMJ）的退化，α-运动之间形成的突触神经元和骨骼肌纤维，最终导致与年龄相关的运动功能障碍。躯体运动系统的输出，NMJ的退化不可避免地导致退化运动轴突的损伤和肌纤维的萎缩，从而影响随意运动。使用 R56 补助金来确定维持和修复 NMJ 的因素至关重要。由NIA提供，我们实验室鉴定出成纤维细胞生长因子结合蛋白1（FGFBP1）作为肌肉纤维分泌的有希望的候选因子，以保持和恢复完整性衰老过程中 NMJ 的作用是陪伴细胞外的 FGF 配体。通过这种方式，它增强了 FGF 信号传导。虽然 FGFBP1 在年轻成年小鼠中集中于 NMJ，但在在正常衰老和 SOD1G93A 小鼠（ALS 小鼠模型）中，我们使用基因敲除小鼠。观察到 FGFBP1 表达对于减缓 NMJ 衰老和运动缺陷是必需的此外，表达 SOD1G93A 的小鼠中 FGFBP1 缺失，这是一个模型。肌萎缩侧索硬化症 (ALS)，加速 NMJ 退化、疾病进展和这些初步发现强烈表明，可以防止内源性的损失。衰老过程中的 FGFBP1 可能足以减缓 NMJ 的退化，从而保护运动功能为了检验这个假设，我们提出了三个相互依赖的具体目标。目标 1，我们检验以下假设：FGFBP1 缺陷小鼠的运动缺陷是由在目标 2 中，我们将寻求确定 NMJ 的细胞、分子和生理变化。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。 FGFBP1 足以预防和逆转 NMJ 的年龄相关变化的假设。这些目标旨在揭示加速 NM 老化的最初变化，即导致衰老肌肉中 FGFBP1 表达降低的分子因素，以及 FGFBP1 在保护 NMJ 和运动功能方面的治疗潜力。