This program will investigate the cellular and molecular regulation of small and large intestinal motility. Significant progress was made during previous funding periods of this program in determining the cellular and molecular components of the neuromuscular apparatus of GI smooth muscles. The program is highly integrated with strong collaborations between participants, and a prolific track-record of publications in neurogastroenterology. We propose 5 projects for the next funding period. Project 1 will investigate the ionic mechanism of electrical rhythmicity in interstitial cells of Cajal (ICC). Specifically the ionic conductance responsible for pacemaker current will be characterized, and we will attempt to determine the molecular entity responsible for pacemaker currents. We will also investigate the Ca 2+ conductance responsible for entrainment of pacemakers in networks of ICC and propagation of electrical activity. Project 2 will investigate some of the specific post-junctional targets of inhibitory neurotransmission in GI muscles. Project 3 will investigate the molecular basis for and physiological function of stretch activated K+ channels. These channels stabilize membrane potential during muscle distension and mediate responses to nitrergic stimulation. Project 4 will investigate the neural circuitry responsible for migrating myoelectrical complexes in GI organs. These are periodic bursts of activity that clear the bowel of undigested contents and guard against bacterial overgrowth. Project 5 will investigate the development and plasticity of ICC. Many human motility disorders have been associated with loss of ICC, and it is important to understand the factors regulating development of ICC and causing loss of ICC in pathophysiological models. The 5 projects of the PPG will be supported by 3 Core facilities. Core A will be an administrative core that will arrange PPG meetings, maintain personnel records, assist with purchasing and travel, and help with grant reporting. Core B is a tissue, cell and cell culture facility that will provide all animals, tissues, dispersed cells, cultured tissues and cells, sorted cells, etc. for the 5 projects. Core C will offer molecular biology and morphology services to PPG projects. The PPG has made important contributions to the field of neurogastroenterology and to the training of young scientists in this field. The next funding period will investigate exciting new hypotheses that may enhance our ability to design effective therapies for GI motility disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK041315-19
Application #
7235352
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (J2))
Program Officer
Hamilton, Frank A
Project Start
1994-05-17
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
19
Fiscal Year
2007
Total Cost
$1,232,064
Indirect Cost
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Durnin, Leonie; Kwok, Benjamin; Kukadia, Priya et al. (2018) An ex vivo bladder model with detrusor smooth muscle removed to analyse biologically active mediators released from the suburothelium. J Physiol :
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Drumm, Bernard T; Sung, Tae S; Zheng, Haifeng et al. (2018) The effects of mitochondrial inhibitors on Ca2+ signalling and electrical conductances required for pacemaking in interstitial cells of Cajal in the mouse small intestine. Cell Calcium 72:1-17
Baker, Salah A; Drumm, Bernard T; Skowronek, Karolina E et al. (2018) Excitatory Neuronal Responses of Ca2+ Transients in Interstitial Cells of Cajal in the Small Intestine. eNeuro 5:
Drumm, Bernard T; Hennig, Grant W; Battersby, Matthew J et al. (2017) Clustering of Ca2+ transients in interstitial cells of Cajal defines slow wave duration. J Gen Physiol 149:703-725
Smith, Terence Keith; Koh, Sang Don (2017) A model of the enteric neural circuitry underlying the generation of rhythmic motor patterns in the colon: the role of serotonin. Am J Physiol Gastrointest Liver Physiol 312:G1-G14
Beckett, Elizabeth A H; Sanders, Kenton M; Ward, Sean M (2017) Inhibitory responses mediated by vagal nerve stimulation are diminished in stomachs of mice with reduced intramuscular interstitial cells of Cajal. Sci Rep 7:44759
Durnin, Leonie; Lees, Andrea; Manzoor, Sheerien et al. (2017) Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 313:G419-G433
Cobine, C A; Hannah, E E; Zhu, M H et al. (2017) ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter. J Physiol 595:2021-2041
Lee, Moon Young; Park, Chanjae; Ha, Se Eun et al. (2017) Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels. PLoS One 12:e0171262

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