Role of Target-derived FGFs in Maintaining and Repairing Synapses

项目总结/摘要 我是弗吉尼亚理工大学Carnival研究所的终身助理教授。 该研究所的跨学科，互动，学院和培育氛围， 有利于发展成功的研究和学术生涯。对我的事业有帮助 目标，我已经组建了一个特殊的导师团队，与迈克尔·弗里德兰德博士（在 VTCRI）担任导师，Kenneth Fischbeck博士（在NINDS）和Michael Fox博士（在 VTCRI）担任共同导师。在短期内，我将获得进一步的培训，获得新的技能， 以及成功运行团队驱动的研究项目所需的经验， 独立的资金来源，包括R 01。这些经历将为我提供 获得终身职位和运行一个非常成功和资金充足的实验室所必需的基础。 在我的实验室里，我将寻求发现和操纵分子， 突触，从而防止运动技能的下降，发生与正常老化和 减弱了许多与年龄相关的神经退行性疾病的影响。在这份提案中，我 假设维持神经肌肉接头（NMJ）的正常功能， 以及实验上可接近的运动神经元和肌肉纤维之间形成的突触， 可能足以减缓或防止由衰老引起的运动技能的侵蚀， 肌萎缩侧索硬化症（ALS）。这一假设源于这样一个事实，即有害的 NMJ的变化似乎先于运动神经元死亡和肌纤维萎缩 在正常衰老和肌萎缩侧索硬化症的发展过程中。在这方面，我收集了初步的 数据表明成纤维细胞生长因子（FGF）信号通路的三个成员， FGF-7/10/22和FGF结合蛋白（FGFBP 1）可能是有希望的候选分子， 保护NMJ免受正常老化和ALS的伤害。在小鼠中，缺失FGF- 22导致NMJ过早老化。它还延迟骨骼肌的神经再支配， 损伤类似地，FGFBP 1的减少延迟骨骼肌的神经再支配。因此这些 结果提示FGF-22和FGFBP 1可能具有修复NMJ的功能。在这个项目中，我 目的是研究这些生长因子在衰老的NMJ中的功能，以及在NMJ的启动和 ALS的进展。除了培训机会外，拟议的实验还可以 导致新的治疗目标和保护运动系统的方法。

Project Summary/Abstract I am a tenure-track assistant professor at the Virginia Tech Carilion Research Institute. The interdisciplinary, interactive, collegial and nurturing atmosphere at the institute is truly conducive for developing a successful research and academic career. To help with my career goals, I have assembled an exceptional team of mentors, with Dr. Michael Friedlander (at VTCRI) serving as a mentor and Dr. Kenneth Fischbeck (at NINDS) and Dr. Michael Fox (at VTCRI) serving as co-mentors. In the short-term, I will obtain further training, acquire new skills and the experience needed to successfully run a team-driven research project and compete for independent sources of funding, including an R01. These experiences will provide me with the foundation necessary to obtain tenure and run a highly successful and well-funded laboratory. In my laboratory, I will seek to discover and manipulate molecules that act to maintain synapses, and thereby prevent the decline of motor skills that occur with normal aging and in blunting the effects of a multitude of age-related neurodegenerative diseases. In this proposal, I hypothesize that maintaining the normal function of the neuromuscular junction (NMJ), a large and experimentally accessible synapse formed between motor neurons and muscles fibers, could be sufficient to slow or prevent the erosion of motor skills caused by aging and amyotrophic lateral sclerosis (ALS). This hypothesis stems from the fact that deleterious changes at the NMJ appears to precede death of motor neurons and atrophy of muscle fibers during the progression of normal aging and ALS. In this regard, I have gathered preliminary data suggesting that three members of the fibroblast growth factor (FGF) signaling pathway, FGF-7/10/22, and a FGF-binding protein (FGFBP1) could be promising candidate molecules for protecting NMJs from insults emanating from normal aging and ALS. In mice, deletion of FGF- 22 results in premature aging of the NMJ. It also delays reinnervation of skeletal muscles after injury. Similarly, a reduction in FGFBP1 delays reinnervation of skeletal muscles. Thus, these results suggest that FGF-22 and FGFBP1 could function to repair the NMJ. In this project, my goal is to investigate the function of these growth factors in aging NMJs and in the initiation and progression of ALS. In addition to the training opportunities, the proposed experiments could lead to new therapeutic targets and approaches for protecting the motor system.