This is a multidisciplinary research program to study, in humans, animals and organotypic tissue culture, selected types of toxin-induced sensory and motor system diseases characterized by degeneration of neurons and/or axons. The program represents the continuation and expansion of long-standing, productive and collaborative efforts by a group of neurologists and neuroscientists trained in anatomy, biochemistry, computer science, pathology, pharmacology, physiology, toxicology and neural tissue culture. These investigators will focus on four closely interrelated and coordinated projects in which plant and synthetic neurotoxic agents are used as defined chemical probes to study molecular and cellular mechanisms underlying neuronal development, maintenance, degeneration and regeneration. Each project receives support from centralized morphology, computer and administrative facilities. Project I and III will study the causation, pathogenetis and treatment of lathyrism, and unexplored human toxic motor-system disease analogous to primary lateral sclerosis. Projects II and III employ acrylamide and 2,5-hexandione to investigate the biochemical, metabolic and cellular mechanisms underlying the onset, evaluation and recovery from central-peripheral distal axonopathy, the pathological hallmark of many system diseases. Projects IV and III utilize taxol and doxorubicin to probe trophic and other factors regulating the development, survival and maintenance of neurons and their target tissues. The experimental investigations complement our ongoing studies of humans with naturally occurring and toxic degenerative system diseases, including lathyrism. The organization of this project is based on our continuing and successful philosophy that meaningful understanding of human neurological disease can often best be achieved with the support of fundamental studies of relevant experiental animal and tissue culture models. The utilization of our novel tissue culture model in two of the four projects is in line with national goals to minimize use of animals in medical research.
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