This research proposal is directed at investigating, on a fundamental level, the pathogenetic mechanism involved in injury to the enteric nervous system caused by diabetes mellitus. Specific experiments are designed to assess the factors controlling growth, differentiation and function of myenteric plexus neurons. the proposed research focuses on an extremely important area which is largely unexplored. The potential applicability to human health and disease is very large. The neuropathologic changes that occur in diabetic autonomic neuropathy have to been clearly established; little is known of he mechanisms involved in their evolution. In addition, little information is available relating pathologic changes to abnormal function. The lack of detailed information regarding the pathogenesis of diabetic enteric neuropathy has several causes: 1. The absence of reproducible and unequivocal neuropathologic changes in commonly used animal models, 2. an investigational focus on somatic nerves rather than the enteric nervous system, 3. the difficulty in studying enteric neurotransmitter in vivo, and, 4. the lack of appropriate in vitro models to explore neurocrine control mechanisms. These difficulties are reflected n the currently empiric, and often unsuccessful, treatment of human diabetic neuropathic disease. The proposed research concentrates on abnormalities of the enteric nervous system of the alimentary tract that are associated with diabetes mellitus. The proposed studies will focus on: 1. changes in neuron populations and enteric neurotransmitter levels caused by diabetes, and 2. elucidation of control mechanisms for neuronal growth differentiation and function that could b affected by diabetes. the proposed research addresses, at a fundamental level, the current deficiency of information about the pathogenesis of this important disease process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041204-04
Application #
3241812
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1988-12-01
Project End
1992-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
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

Showing the most recent 10 out of 17 publications