The enteric nervous system (ENS) resides in the gut wall and controls physiology of the alimentary tract. The majority of the ENS is composed of enteric glial cells (EGCs), which have been linked to a wide range of gut pathologies, e.g., inflammatory bowel disease, necrotizing enterocolitis and """"""""idiopathic"""""""" constipation. Our preliminary data point to a novel hypothesis that EGCs support normal gut function through their cell-cell connectivity established via connexin 43;the down regulation of Cx43 leads to inflammatory morphological changes and reduced motility of the gut. To test this hypothesis we will use an innovative molecular genetics approach integrated with histology, fiber-optic colonoscopy, GI transit tests in vivo, and an ex vivo imaging method of an isolated colon. This proposed investigation will gather valuable information on the novel role of Cx43 in the function of the gut and ENS. These findings will be of general interest to neurobiology. Additionally, the findings will be relevant to translational medicine, since they could open the door for the development of a cause-directed treatment for constipation and various inflammatory bowel diseases. These potential new opportunities for intervention could greatly improve clinical practice in gastroenterology by increasing the survival rate of neonatal patients suffering from necrotizing enterocolitis and substantially improve the quality of life and survival in the other ENS/EGC related gut pathologies.

Public Health Relevance

This proposed investigation will gather valuable information on the novel role of connexin 43 in the function of the gut and these findings will be of general interest to neurobiology. They will also be relevant to translational medicine, since they could open the door to development of cause-directed treatment for constipation and various inflammatory bowel diseases. These new potential treatments could greatly improve clinical practice in gastroenterology by increasing the survival rate of neonatal patients suffering from necrotizing enterocolitis and substantially improving the quality of life and survival in the other gut pathologies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD078678-01
Application #
8619205
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Grave, Gilman D
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$220,500
Indirect Cost
$70,500
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Grubiši?, Vladimir; Parpura, Vladimir (2017) Two modes of enteric gliotransmission differentially affect gut physiology. Glia 65:699-711
Zorec, R; Parpura, V; Verkhratsky, A (2017) Astroglial vesicular network: evolutionary trends, physiology and pathophysiology. Acta Physiol (Oxf) :
Verkhratsky, Alexei; Zorec, Robert; Parpura, Vladimir (2017) Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27:629-644
Verkhratsky, Alexei; Rodríguez-Arellano, J J; Parpura, Vladimir et al. (2017) Astroglial calcium signalling in Alzheimer's disease. Biochem Biophys Res Commun 483:1005-1012
Lee, William; Parpura, Vladimir (2016) Spatio-temporal characteristics of metabotropic glutamate receptor 5 traffic at or near the plasma membrane in astrocytes. Glia 64:1050-65
Verkhratsky, Alexei; Zorec, Robert; Rodríguez, Jose J et al. (2016) Astroglia dynamics in ageing and Alzheimer's disease. Curr Opin Pharmacol 26:74-9
Rodríguez-Arellano, J J; Parpura, V; Zorec, R et al. (2016) Astrocytes in physiological aging and Alzheimer's disease. Neuroscience 323:170-82
Vardjan, Nina; Parpura, Vladimir; Zorec, Robert (2016) Loose excitation-secretion coupling in astrocytes. Glia 64:655-67
Verkhratsky, Alexei; Zorec, Robert; Rodriguez, Jose J et al. (2016) PATHOBIOLOGY OF NEURODEGENERATION: THE ROLE FOR ASTROGLIA. Opera Med Physiol 1:13-22
Verkhratsky, Alexei; Steardo, Luca; Parpura, Vladimir et al. (2016) Translational potential of astrocytes in brain disorders. Prog Neurobiol 144:188-205

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