This is the second competitive renewal of a multidisciplinary, interdependent research program designed to explore the etiology and pathogenesis of major neurodegenerative disorders. The program is the continuation of productive and collaborative efforts by a group of clinically sensitive basic neuroscientists with a wide variety of investigative skills. These colleagues will focus on four interdependent projects in which natural and synthetic chemical agents are used as defined chemical probes to study molecular and cellular mechanisms underlying the selective degeneration of mammalian neurons and/or axons. Specific focus will be placed on elucidating mechanisms underlying self-limiting and progressive neurogenerative disease models, acrylamide neuropathy, Lathyrism (beta-N-oxalylamino-L-alanine), Amnestic Shellfish Poisoning (domoic acid) and, notably, the cycad-linked and amyloid-associated Western Pacific amyotrophic lateral sclerosis/Parkinsonism-dementia complex. Project I will collect and analyze cycad seed for chemical components with DNA-binding and neuronotoxic properties. Core A will synthesize authentic samples of defined cycad neurotoxins for distribution to colleagues who will study their actions on neuronal excitatory mechanisms (Project II), on axonal transport (III), and on gene expression (IV). Project II will employ neurophysiological, neurochemical and morphological methods to examine in neuronal cultures the relationship between biological toxins, the development of neuronal excitatory amino acid receptors, and the distribution of neuronal damage in human motor-system disorders. Project III is focused on the pathophysiological and neurochemical changes in axonal transport and neuronal perikarya which underly primary axonal degeneration induced in animals by the occupational toxin acrylamide. The projects variously rely on Core A technical services, including chemical synthesis, cell and tissue culture, animal behavior and neuropathology. These experimental investigations complement ongoing studies of humans with idiopathic and toxin-associated neurodegenerative diseases. The organization of this program is based on a continuing and successful philosophy that meaningful understanding of human neurological disease is best achieved with the support of laboratory and field studies. Prevention of neurodegenerative disorders through an understanding of etiology is the long-term goal.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Neurological Disorders Program Project Review B Committee (NSPB)
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Oregon Health and Science University
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Esclaire, F; Kisby, G; Spencer, P et al. (1999) The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity. Exp Neurol 155:11-21
Tor-Agbidye, J; Palmer, V S; Lasarev, M R et al. (1999) Bioactivation of cyanide to cyanate in sulfur amino acid deficiency: relevance to neurological disease in humans subsisting on cassava. Toxicol Sci 50:228-35
Omelchenko, I A; Jain, R K; Junaid, M A et al. (1999) Neurotoxic potential of three structural analogs of beta-N-oxalyl-alpha,beta-diaminopropanoic acid (beta-ODAP). Neurochem Res 24:791-7
Spencer, P S (1999) Food toxins, ampa receptors, and motor neuron diseases. Drug Metab Rev 31:561-87
Kisby, G E; Kabel, H; Hugon, J et al. (1999) Damage and repair of nerve cell DNA in toxic stress. Drug Metab Rev 31:589-618
Tor-Agbidye, J; Palmer, V S; Sabri, M I et al. (1998) Dietary deficiency of cystine and methionine in rats alters thiol homeostasis required for cyanide detoxification. J Toxicol Environ Health A 55:583-95
Omelchenko, I A; Nelson, C S; Allen, C N (1997) Lead inhibition of N-methyl-D-aspartate receptors containing NR2A, NR2C and NR2D subunits. J Pharmacol Exp Ther 282:1458-64
Gold, B G (1997) Axonal regeneration of sensory nerves is delayed by continuous intrathecal infusion of nerve growth factor. Neuroscience 76:1153-8
Kisby, G E; Milne, J; Sweatt, C (1997) Evidence of reduced DNA repair in amyotrophic lateral sclerosis brain tissue. Neuroreport 8:1337-40
Wang, M S; Zeleny-Pooley, M; Gold, B G (1997) Comparative dose-dependence study of FK506 and cyclosporin A on the rate of axonal regeneration in the rat sciatic nerve. J Pharmacol Exp Ther 282:1084-93

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