Role of Target-derived FGFs in Maintaining and Repairing Synapses

职位描述(由申请人提供)：我是弗吉尼亚理工大学卡里昂研究所的终身教职助理教授。该研究所的跨学科、互动、合作和培养的氛围真正有利于发展成功的研究和学术事业。为了帮助实现我的职业目标，我组建了一支杰出的导师团队，由VTCRI的Michael Friedlander博士担任导师，NINDS的Kenneth Fischbeck博士和VTCRI的Michael Fox博士担任共同导师。在短期内，我将获得进一步的培训，获得成功运行团队驱动的研究项目所需的新技能和经验，并竞争独立的资金来源，包括R01。这些经验将为我提供必要的基础，以获得终身教职，并运营一个非常成功和资金充足的实验室。在我的实验室里，我将寻求发现和操纵维持突触的分子，从而防止运动技能的下降，这些技能随着正常衰老而发生，并削弱许多与年龄相关的神经退行性疾病的影响。在这项提议中，我假设维持神经肌肉接头(NMJ)的正常功能，一个在运动神经元和肌肉纤维之间形成的大型且可通过实验获得的突触，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。这一假说源于这样一个事实：在正常衰老和ALS的发展过程中，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，我已经收集了初步的数据，表明成纤维细胞生长因子信号通路的三个成员，成纤维细胞生长因子-7/10/22和成纤维细胞生长因子结合蛋白(FGFBP1)可能是保护NMJ免受正常衰老和ALS产生的损伤的候选分子。在小鼠中，FGF-22的缺失会导致NMJ的过早老化。它还会推迟骨骼肌在受伤后的神经再支配。类似地，FGFBP1的减少会延迟骨骼肌的神经再支配。因此，上述结果提示，FGFBP1和FGFBP1可能具有修复NMJ的作用。在这个项目中，我的目标是研究这些生长的功能 NMJ老化和ALS发生发展的因素。除了培训机会，拟议中的实验可能会带来新的治疗目标和保护运动系统的方法。

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.