NEUROTOXIC PROBES OF MOTOR AND SENSORY SYSTEM DISEASES

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.