Studies performed in the past decade indicate that the intrinsic nervous system of the alimentary tract regulates nearly every aspect of digestion. Emerging evidence also indicates that the enteric nervous system may be vulnerable to injury from a variety of causes. In most instances, the neuropathological changes that underlie human disorders have not been clearly established, and little is known of the mechanisms involved in their evolution. These deficiencies are reflected in the currently empiric, and often ineffective, treatment of human enteric neuropathic disease. The research program supported by this grant has focused upon this lack of information. Using novel in vitro approaches, studies have examined enteric neuronal growth, functional development, and neurotransmitter release. Technical refinements have permitted the examination of small amounts of tissue, to the level of individual cells. Physiologic correlations have been possible. The current proposal extends these investigations. In the current proposal the investigators hypothesize that: 1) enteric neurons respond to excitatory neurotransmitters by increasing intracellular calcium; 2) glial cells also respond to neuroligands by modulation of intracellular calcium; 3) intercellular signaling occurs both by release of neurotransmitter molecules and by direct cell-to-cell contact; 4) signaling pathways in enteric neurons and glia are linked to distinct systems of cellular activation and functional response. This proposal seeks to address, at a fundamental level, the deficiency of information about the enteric nervous system.
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