This Program Project seeks to understand basic cellular mechanisms responsible for gastrointestinal (Gl) motility. Knowledge of the basic structures and mechanisms of the neuromuscular apparatus of the Gl tract provides insights about how normal Gl motility is accomplished and why dysmotilities develop in the abnormal Gl tract. The long range benefit of this information will be to provide the basis for novel methods for treatment of abnormal Gl transit and to improve the quality of life for human patients. The neuromuscular apparatus of the Gl tract is extremely complex and function depends upon integrated activity of several types of cells. We have designed 4 projects that will explore various aspects of enteric neurotransmission, pacemaker activity, and smooth muscle function. Project 1, using a novel murine genetic model in which interstitial cells of Cajal (ICC) express a fluorescent protein, will seek to understand the mechanism of pacemaker activity and how pacemaker function is affected in diabetes and ICC hyperplasia. Project 3 will seek to understand regulation of smooth muscle excitability and how the activity of non-selective cation conductances contributes to normal and abnormal responses of muscle cells. Project 4 will investigate the release, function and metabolism of a novel neurotransmitter substance that is important for regulating colonic motor function. Project 5 will study the plasticity of ICC and how and why these cells are lost in type II diabetes. This project will also seek to develop techniques for restoring networks of ICC after damage. These primary investigations will be supported by 3 Core facilities designed to provide administration and informatics support and cutting-edge techniques, including cell and organotypic cultures, construction of transgenic animals, cytometry and fluorescence activated cell sorting, analysis of molecular expression, and a variety of morphological techniques. For the purpose of translating our findings from animal models to the function of the human Gl tract, many of our experiments will be conducted on tissues and cells of human patients that have been recovered from surgery for carcinomas. The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery

Public Health Relevance

This Program Project seeks to understand the basic motor components of the gastrointestinal (Gl) tract that are responsible for orderly processing of food and wastes. Coordinated Gl movements are a basic necessity of life, yet millions of American patients suffer from diseases of poorly regulated Gl transit. At present there are inadequate therapies available to relieve the suffering and, in some cases life threatening conditions, endured bv these patients.

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-9 (J1))
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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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