Axonal degeneration, or death of nerve fibers, is the most common pathological finding in the majority of neurological disorders, including stroke, head and spinal cord trauma, and peripheral neuropathy. There is a paucity of data regarding the basic mechanisms of axonal degeneration, and it is unclear whether axonal death in each of these disorders occurs via multiple or common pathways. Experimental studies, however, support the idea that calcium entry and protease activation are important. The long term goal of these studies is to understand the basic mechanisms leading to axonal degeneration using clinically relevant models of disease, and to use these new data to direct strategies for prevention of axonal degeneration and thus preservation of neurological function. The experimental design exploits: 1) the sensory ganglia culture system for manipulating rodent axons in a reproducible in vitro setting, and 2) the WLD mouse, a unique mutant strain whose sole phenotype is resistance to traumatic axonal degeneration.
Aim 1 will test the hypothesis that axonal death caused by trauma (axotomy) and exposure to a neurotoxin (vincristine) occurs by a common mechanism involving calcium entry and activation of the protease, calpain.
In Aim 2, axons from the WLD mouse which are resistant to axotomy-induced degeneration will be used to further test the hypothesis stated in Aim 1. These axons will be tested for their ability to resist degeneration when exposed to a neurotoxin induced axonal degeneration.
Aim 3 will ask when calcium entry and calpain activation occur after nerve injury, and what relationship these events have to axonal degeneration.
Aim 3 will ask when calcium entry and calpain activation occur after nerve injury, and what relationship these events have to axonal degeneration. Using state-of-the-art imaging techniques, the proximal and distal portions of transected nerve fibers will be compared since they are exposed to the same injury, but one survives and the other dies.
Aim 4 is directed at identifying proteases other than calpain that are present and active in degenerating nerve fibers, with the premise that a directed strategy for preventing axonal degeneration during disease requires an intimate understanding of all of the processes involved. Overall, the achievement of these Aims will provide a new appreciation of the mechanisms of axonal degeneration that will certainly impact on treatment strategies for a number of brain, spinal cord, and peripheral nerve diseases.
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