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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-6 (J3))
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Hamilton, Frank A
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University of Nevada Reno
Schools of Medicine
United States
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Sanders, Kenton M; Salter, Anna K; Hennig, Grant W et al. (2014) Responses to enteric motor neurons in the gastric fundus of mice with reduced intramuscular interstitial cells of cajal. J Neurogastroenterol Motil 20:171-84
Zheng, Haifeng; Park, Kyung Sik; Koh, Sang Don et al. (2014) Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine. Am J Physiol Cell Physiol 306:C705-13
McCann, Conor J; Hwang, Sung-Jin; Hennig, Grant W et al. (2014) Bone Marrow Derived Kit-positive Cells Colonize the Gut but Fail to Restore Pacemaker Function in Intestines Lacking Interstitial Cells of Cajal. J Neurogastroenterol Motil 20:326-37
Durnin, Leonie; Hwang, Sung Jin; Kurahashi, Masaaki et al. (2014) Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut. Proc Natl Acad Sci U S A 111:15821-6
Okamoto, T; Barton, M J; Hennig, G W et al. (2014) Extensive projections of myenteric serotonergic neurons suggest they comprise the central processing unit in the colon. Neurogastroenterol Motil 26:556-70
Drumm, Bernard T; Koh, Sang Don; Andersson, Karl-Erik et al. (2014) Calcium signalling in Cajal-like interstitial cells of the lower urinary tract. Nat Rev Urol 11:555-64
Mutafova-Yambolieva, Violeta N; Durnin, Leonie (2014) The purinergic neurotransmitter revisited: a single substance or multiple players? Pharmacol Ther 144:162-91
Sanders, Kenton M; Ward, Sean M; Koh, Sang Don (2014) Interstitial cells: regulators of smooth muscle function. Physiol Rev 94:859-907
Kurahashi, Masaaki; Nakano, Yasuko; Peri, Lauren E et al. (2013) A novel population of subepithelial platelet-derived growth factor receptor *-positive cells in the mouse and human colon. Am J Physiol Gastrointest Liver Physiol 304:G823-34
Keef, K D; Saxton, S N; McDowall, R A et al. (2013) Functional role of vasoactive intestinal polypeptide in inhibitory motor innervation in the mouse internal anal sphincter. J Physiol 591:1489-506

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