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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG7-SAT (01))
Program Officer
May, Michael K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
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

Showing the most recent 10 out of 17 publications