18 GOALS FOR FELLOWSHIP TRAINING AND CAREER I have long been interested in the development of the nervous system and how the nervous system responds to, and recovers from, injury I chose to pursue an MD/PhD to better understand these processes on both a basic and a clinical level My goal in undertaking this research fellowship is to hone my skills in identifying important, relevant questions in my field of interest, to learn to develop a practical but thorough research plan that addresses important questions in a critical manner, and to continue develop my ability to critically evaluate my work and that of others While my training in confocal and in vivo microscopy, molecular biology and electrophysiology will be of value in my future work, I believe that working at the interface of basic and clinical issues will help me in my future career as a physician- scientist SPONSOR 19 NAME AND DEGREE(S) Rita J. Balice-Gordon, Ph.D. '20 POSITION/RANK Associate Professor 21 RESEARCHINTERESTS/AREAS Synapse formation, synaptic plasticity, neuromuscular junctions, gap junctions, and cell-cell signaling, neurotrophins, reinnervation :_;1.1f;:1,(oi-'I -.,tI,(o]-.,[o]f ;t 22 DESCRIPTION (Do notexceedspace provided) This proposal is aimed at determining the role of neurotrophins that signal through Trk receptors in modulating synapse structure and function in the developing and adult nervous system, using mouse neuromuscular synapses as a model system The cell types that comprise neuromuscular junctions, the perisynaptic Schwann cells, presynaptic motor neuron terminals, and postsynaptic muscle fibers, each express a distinct complement of neurotrophins and Trks This suggests that neurotrophin signaling at this synapse is muki-directional and involves all three cell types, but the relative roles of each signaling pathway in synaptic structure and function are unclear Previous work from the Balice-Gordon lab has shown that TrkB, which binds the neurotrophins BDNF and NT4/5, is expressed primarily postsynaptically in the muscle fibe! membrane adjacent to acetylcholine receptor (AChR) clusters Down-regulation of TrkB signaling in muscle fibers induced the disassembly of AChR clusters These observations lead to the hypothesis that exchange of ligands that signal through TrkB receptors modulates neuromuscular synaptic structure and function To determine the lole of these signaling molecules at synapses, it will be essential to selectively delete TrkB or neurotrophin fiom one of the cell types at neuromuscular synapses Because many null mutant mice die perinatally, I propose to use C_e-mediated recombination to delete BDNF or TrkB from cells of interest in a spatially and temporally controlled fashion The effects of these deletions on neuromuscular synaptic structure, function, axon regrowth and synaptic reinnervation after injury will be analyzed with in vivo imaging, immunostaining, confocal microscopy and electrophysiological characterization of synaptic strength The results of these experiments will provide new insights into the functional roles of neurotrophin and Trk-mediated signaling at developing, adult and injured synapses PHS416-1 (Rev 12/98) FormPage 2 BB CC IndividualNRSApplication Table of Contents ========================================Section End===========================================
| Hess, Darren M; Scott, Marion O; Potluri, Srilatha et al. (2007) Localization of TrkC to Schwann cells and effects of neurotrophin-3 signaling at neuromuscular synapses. J Comp Neurol 501:465-82 |
| Pitts, Elizabeth Vernon; Potluri, Srilatha; Hess, Darren M et al. (2006) Neurotrophin and Trk-mediated signaling in the neuromuscular system. Int Anesthesiol Clin 44:21-76 |
| Su, Yuhua; Balice-Gordon, Rita J; Hess, Darren M et al. (2004) Neurobeachin is essential for neuromuscular synaptic transmission. J Neurosci 24:3627-36 |
