Novel approaches to neural regeneration: Defining new genes & pathways

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Project Summary - Neuronal injury, such as spinal cord damage, is devastating and typically leads to extreme reduction in life quality. Spinal cord injuries alone affect ~15,000 people/year in the US; about 10,000 of these patients will be permanently paralyzed and many others die due to their injuries. Few approaches are available to treat such devastating injuries, in large part because little is clear about biological pathways & genes that influence regeneration, due to the complexity of the process and the limited systems available for attacking the problem. New insight may be applicable not only to spinal cord injury, but also to brain trauma, stroke and neurodegenerative disease. We propose to develop one of the premier model organism systems-Drosophila-as a new experimental paradigm for adult-stage neural regeneration. In pilot studies in living adult animals, we have severed the wing nerve bundle with a laser and observed degeneration of the nerve tract. Striking preliminary observations show that after a 3-week quiescent period, the nerve bundle regenerates in about 40% of the animals. We will perform detailed characterization of this nerve injury experimental paradigm, including extent and speed of degeneration, as well as extent, speed and accuracy of regeneration. Then, using this system, we will exploit the available sets of molecularly-defined gene mutants in the fly to identify new genes & pathways. Because the baseline regeneration appears partial, this experimental paradigm will reveal both pathways that influence degeneration, as well as those that modulate regeneration. These studies will establish a new experimental paradigm for regeneration studies, and reveal new molecules & pathways, providing basic biological insight and the foundation for discovery of novel therapeutics for nerve injury, damage and degenerative disease.