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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology C Study Section (NEUC)
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Massachusetts General Hospital
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McConalogue, K; Furness, J B; Vremec, M A et al. (1995) Histochemical, pharmacological, biochemical and chromatographic evidence that pituitary adenylyl cyclase activating peptide is involved in inhibitory neurotransmission in the taenia of the guinea-pig caecum. J Auton Nerv Syst 50:311-22
Portbury, A L; McConalogue, K; Furness, J B et al. (1995) Distribution of pituitary adenylyl cyclase activating peptide (PACAP) immunoreactivity in neurons of the guinea-pig digestive tract and their projections in the ileum and colon. Cell Tissue Res 279:385-92
Furness, J B; Young, H M; Pompolo, S et al. (1995) Plurichemical transmission and chemical coding of neurons in the digestive tract. Gastroenterology 108:554-63
McConalogue, K; Lyster, D J; Furness, J B (1995) Electrophysiological analysis of the actions of pituitary adenylyl cyclase activating peptide in the taenia of the guinea-pig caecum. Naunyn Schmiedebergs Arch Pharmacol 352:538-44
Messenger, J P; Furness, J B; Trudrung, P (1994) Locations of postganglionic nerve cells whose axons enter nerves originating from prevertebral ganglia. Arch Histol Cytol 57:405-13
Wardell, C F; Bornstein, J C; Furness, J B (1994) Projections of 5-hydroxytryptamine-immunoreactive neurons in guinea-pig distal colon. Cell Tissue Res 278:379-87
McConalogue, K; Furness, J B (1993) Projections of nitric oxide synthesizing neurons in the guinea-pig colon. Cell Tissue Res 271:545-53
Young, H M; McConalogue, K; Furness, J B et al. (1993) Nitric oxide targets in the guinea-pig intestine identified by induction of cyclic GMP immunoreactivity. Neuroscience 55:583-96
Young, H M; Furness, J B; Shuttleworth, C W et al. (1992) Co-localization of nitric oxide synthase immunoreactivity and NADPH diaphorase staining in neurons of the guinea-pig intestine. Histochemistry 97:375-8
Ciulla, T A; Sklar, R M; Hauser, S L (1988) A simple method for DNA purification from peripheral blood. Anal Biochem 174:485-8

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