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

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK041204-13
Application #
6286596
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
May, Michael K
Project Start
1988-12-01
Project End
2005-11-30
Budget Start
2001-02-01
Budget End
2001-11-30
Support Year
13
Fiscal Year
2001
Total Cost
$342,192
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chai, B; Li, J-Y; Fritze, D et al. (2013) A novel transcript is up-regulated by fasting in the hypothalamus and enhances insulin signalling. J Neuroendocrinol 25:292-301
Lin, Theodore; Zhang, Weizhen; Fan, Yongyi et al. (2007) Interleukin-1beta and interleukin-6 stimulate matrix metalloproteinase-9 secretion in cultured myenteric glia. J Surg Res 137:38-45
Fan, Yongyi; Zhang, Weizhen; Mulholland, Michael (2005) Thrombin and PAR-1-AP increase proinflammatory cytokine expression in C6 cells. J Surg Res 129:196-201
Segura, Bradley J; Zhang, Weizhen; Xiao, Liqun et al. (2005) Sphingosine-1-phosphate induces early response gene expression in C6 glioma cells. Brain Res Mol Brain Res 133:325-8
Segura, B J; Zhang, W; Xiao, L et al. (2004) Sphingosine-1-phosphate mediates calcium signaling in guinea pig enteroglial cells. J Surg Res 116:42-54
Segura, B J; Zhang, W; Cowles, R A et al. (2004) Lysophosphatidic acid stimulates calcium transients in enteric glia. Neuroscience 123:687-93
Lin, T; Zhang, W; Garrido, R et al. (2003) The role of the cytoskeleton in capacitative calcium entry in myenteric glia. Neurogastroenterol Motil 15:277-87
Turner, D J; Segura, B J; Cowles, R A et al. (2001) Functional overlap of IP(3)- and cADP-ribose-sensitive calcium stores in guinea pig myenteric neurons. Am J Physiol Gastrointest Liver Physiol 281:G208-15
Sarosi, G A; Barnhart, D C; Turner, D J et al. (1998) Capacitative Ca2+ entry in enteric glia induced by thapsigargin and extracellular ATP. Am J Physiol 275:G550-5
Zhang, W; Sarosi Jr, G A; Barnhart, D C et al. (1998) Endothelin-stimulated capacitative calcium entry in enteric glial cells: synergistic effects of protein kinase C activity and nitric oxide. J Neurochem 71:205-12

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