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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK041315-25
Application #
8469473
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (J1))
Program Officer
Hamilton, Frank A
Project Start
1997-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
25
Fiscal Year
2013
Total Cost
$1,238,111
Indirect Cost
$356,893
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Baker, Salah A; Drumm, Bernard T; Saur, Dieter et al. (2016) Spontaneous Ca(2+) transients in interstitial cells of Cajal located within the deep muscular plexus of the murine small intestine. J Physiol 594:3317-38
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
Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe. J Physiol 594:1515
Hwang, Sung Jin; Basma, Naseer; Sanders, Kenton M et al. (2016) Effects of new-generation inhibitors of the calcium-activated chloride channel anoctamin 1 on slow waves in the gastrointestinal tract. Br J Pharmacol 173:1339-49
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
Sanders, Kenton M (2015) New Molecular Tools to Investigate the Development and Functions of Interstitial Cells of Cajal in the GI Tract. Gastroenterology 149:283-6
Peri, Lauren E; Koh, Byoung H; Ward, Grace K et al. (2015) A novel class of interstitial cells in the mouse and monkey female reproductive tracts. Biol Reprod 92:102
Baker, Salah A; Hennig, Grant W; Ward, Sean M et al. (2015) Temporal sequence of activation of cells involved in purinergic neurotransmission in the colon. J Physiol 593:1945-63
Zhu, Mei Hong; Sung, Tae Sik; O'Driscoll, Kate et al. (2015) Intracellular Ca(2+) release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal. Am J Physiol Cell Physiol 308:C608-20

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