Several in vivo and in vitro studies suggest that muscle-derived factors influence the development and the maintenance of synaptic contacts at the neuromuscular junction. Using a chick system, this project will focus on the characterization of such """"""""motoneuron growth factors"""""""" in order to help clarify the relationship between the neuron and its muscle target, and perhaps to provide new insights into the pathogenesis and treatment of human diseases in which motoneurons are selectively lost, such as Amyotrophic Lateral Sclerosis (ALS). Monoclonal antibodies will be produced against a neurite-promoting factor for spinal neurons which is present in chick neonatal muscle extracts. In preliminary work, a 10-4 fold purification of neonatal factor has been achieved, and this material will be used as the starting immunogen. These monoclonal antibodies will then be used to purify the factor to homogeneity, to characterize the active molecule, and to study its function and tissue distribution in normal and in disease states. A second approach is based upon the observation that repeated immunizations with chick neonatal muscle extracts partially purified for neurite-promoting activity can result, in rabbits, in a progressive paralytic disease with prominent atrophy; pathologic examination has revealed a pattern of abnormalities consistent with distal denervation. The immunopathologic mechanisms and the active substances responsible for this syndrome will be studied. Finally the functional effect of circulating antibodies from patients with motor system disease on in vitro neurite extension by dissociated chick spinal cord cells, and the binding of these antibodies to muscle or to nervous system structures will be studied. The purification of neurite-promoting or of disease-inducing substances from muscle will permit direct testing of antibody reactivity against these substances in human disease states.
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