Role of Target-derived FGFs in Maintaining and Repairing Synapses

Virginia Polytechnic Inst And St Univ, Blacksburg VA

Investigators

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Abstract

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.