This is a Program Project to investigate the basic regulatory mechanisms of colonic motility. Initial observations from the Program Director's laboratory have described the diversity of electrical and mechanical behavior through the muscularis of the canine colon. Experiments proposed in this application will investigate the basis for electrical and mechanical heterogeneity in the colon. The thread of the Program runs from neural organization and regulation of electrical and mechanical activity to molecular regulation of contractile proteins. Project 1 will investigate neural control of specific regions of the muscularis and attempt to determine the organization of intrinsic and extrinsic inputs. Project 2 will study the source and propagation of myogenic electrical activity and attempt to isolate the cell-type responsible for pacemaker activity. Project 3 will study the ionic currents underlying electrical activity and the regulation of these currents by agonists and second messengers. Project 4 will study Ca-activated K channels. Preliminary data suggests that these channels may be an important site of action for neurotransmitters. Project 5 will study receptor distribution through the muscularis and the coupling of receptors to responses. Results will provide information about 2nd messenger mobilization. Project 6 will study the source and dynamics of Ca 2+ signaling. State-of-the-art fluorescence measurements will allow real-time monitoring of [Ca2+]i during spontaneous electrical activity and agonist-evoked responses. Project 7 will investigate molecular regulation of contraction. Studies will correlate protein phosphorylation with the development of force and determine which proteins serve as regulators of contraction. This is a unique Program Project because most of the Principal Investigators have just recently become involved in studies of colonic smooth muscle. In effect this Program Project will recruit several talented investigators into the field of gastrointestinal motility. Fresh ideas and rigorous, state-of-the-art research tools will be brought together into a focused investigation of the basic functions of colonic muscle. The broad knowledge of the Principal Investigators about excitable and contractile cells will greatly enrich our knowledge about colonic motility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK041315-02
Application #
3095578
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1989-05-15
Project End
1994-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Nevada Reno
Department
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 :
Shi, Junchao; Ko, Eun-A; Sanders, Kenton M et al. (2018) SPORTS1.0: A Tool for Annotating and Profiling Non-coding RNAs Optimized for rRNA- and tRNA-derived Small RNAs. Genomics Proteomics Bioinformatics 16:144-151
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:
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
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

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