This Program Project grant is designed to enhance our understanding of the basic mechanisms responsible for gastrointestinal (Gl) motility. Knowledge of mechanisms that generate normal motility patterns will help explain what goes awry in motility disorders and develop novel approaches to therapies. In this Program we are investigating smooth muscle cells, Interstitial cells of Cajal (ICC) and PDGFRa+ cells of Gl muscles, which through electrical coupling, form a syncytial tissue we refer to as the SIP syncytium. Cells of the SIP syncytium generate electrical pacemaker activity and provide what has been known as 'myogenic'regulation of motility. SIP cells also receive and transduce inputs from enteric motor neurons, so they are key participants in neural regulation of motility. We have developed techniques to isolate and purify each class of cell in the SIP syncytium, and we have performed deep sequencing of the gene transcripts in these cells. Hypotheses in this proposal were developed from this unprecedented knowledge of the cell-specific transcriptomes of SIP cells. Four projects will investigate questions regarding the mechanism of pacemaking and propagation of electrical slow waves, integration of excitatory responses by ICC and smooth muscle cells in generation of propulsive colonic contractions, bioactivity and targets of purines released and metabolites produced in colonic muscles, and the fate and recovery of ICC in patho-physiological conditions causing loss of ICC. Three Core laboratories will support these projects. Core A will provide informatics support and aide investigators with experimental planning and data management. Core B will provide transgenic animal, isolate and sort cells by fluorescence activated cell sorting, and support organ cultures. Core C will analyze expression of genes and proteins in cells and tissues. Experiments will utilize transgenic mice as model organisms to test novel hypotheses. Ideas developed in rodent studies will be tested on cells and muscles of non-human primates and human patients. The research team is highly synergistic and collaborative and has a long track record of productivity and innovative contributions to neurogastroenterology.
Intestinal motility and the orderly movement of nutrients and wastes in the gastrointestinal tract is problematic for many human patients. Therapies and treatments for motility disorders are scarce, and this is because too little is understood about basic mechanisms regulating motility. This program is investigating pacemaker activity, neural control of motility and what happens to pacemaker cells in disease.
|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|
|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|
|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|
|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|
|Sung, Tae Sik; O'Driscoll, Kate; Zheng, Haifeng et al. (2016) Influence of intracellular Ca2+ and alternative splicing on the pharmacological profile of ANO1 channels. Am J Physiol Cell Physiol 311:C437-51|
|Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe. J Physiol 594:1515|
|Durnin, L; Moreland, N; Lees, A et al. (2016) A commonly used ecto-ATPase inhibitor, ARL-67156, blocks degradation of ADP more than the degradation of ATP in murine colon. Neurogastroenterol Motil 28:1370-81|
|Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) CrossTalk proposal: Interstitial cells are involved and physiologically important in neuromuscular transmission in the gut. J Physiol 594:1507-9|
|Durnin, Leonie; Hayoz, Sebastien; Corrigan, Robert D et al. (2016) Urothelial purine release during filling of murine and primate bladders. Am J Physiol Renal Physiol 311:F708-F716|
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