The intrinsic nervous system of the gastrointestinal tract affects nearly every aspect of digestive activity. While autonomic gastrointestinal dysfunction has been postulated to cause or complicate diseases diverse as intestinal dysmotility and chronic pancreatitis, relatively little is known of the factors controlling signal processing and function of the enteric nervous system. Evidence developed during the current funding period indicates that sphingolipid metabolites, bioactive mediators generated from membrane phospholipids, may have crucial integrative functions in this system. The current proposal is designed to investigate, on a fundamental level, neural control mechanisms that have relevance to human health and disease. The specific hypotheses are that 1 ) enteric neurons and glial cells respond to extracellular sphingolipids via specific receptor-linked pathways; 2) sphingolipids may also act as intracellular signaling molecules; 3) intracellular signaling occurs by both paracrine release of sphingolipids and via extrasynaptic connections; and 4) signaling pathways in enteric neurons and glia are linked to distinct systems of cellular activation and functional response. The proposed research combines physiologic studies with novel cellular and molecular strategies, an approach that is likely to yield important new insights
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