Role of Target-derived FGFs in Maintaining and Repairing Synapses

描述（由申请人提供）：我是弗吉尼亚理工大学卡里隆研究所的终身助理教授。学院的跨学科、互动、合议和培养氛围确实有助于发展成功的研究和学术生涯。为了帮助实现我的职业目标，我组建了一个杰出的导师团队，迈克尔·弗里德兰德博士（在VTCRI）是我的导师，肯尼斯·菲什贝克博士（在NINDS）和迈克尔·福克斯博士（在VTCRI）是共同导师。在短期内，我将获得进一步的培训，获得新的技能和经验，以成功地运行一个团队驱动的研究项目，并争取独立的资金来源，包括R01。这些经历将为我获得终身教职和管理一个非常成功且资金充足的实验室奠定必要的基础。在我的实验室里，我将寻求发现和操纵维持突触的分子，从而防止正常衰老过程中出现的运动技能下降，并减弱许多与年龄相关的神经退行性疾病的影响。在这个提议中，我假设维持神经肌肉连接（NMJ）的正常功能，运动神经元和肌肉纤维之间形成的一个大的、实验上可获得的突触，足以减缓或防止由衰老和肌萎缩侧索硬化症（ALS）引起的运动技能的侵蚀。这一假设源于这样一个事实，即在正常衰老和渐缩性脊髓侧索硬化症的进程中，NMJ的有害变化似乎先于运动神经元的死亡和肌肉纤维的萎缩。在这方面，我收集的初步数据表明，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（FGFBP1）可能是保护NMJs免受正常衰老和渐冻症损伤的有希望的候选分子。在小鼠中，FGF- 22的缺失导致NMJ的过早衰老。它也延迟骨骼肌损伤后的神经再支配。同样，FGFBP1的减少会延迟骨骼肌的再神经支配。因此，这些结果表明FGF-22和FGFBP1可能具有修复NMJ的功能。在这个项目中，我的目标是研究这些生长的功能

DESCRIPTION (provided by applicant): 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.