A number of Gl symptoms and motility disorders, including idiopathic inflammatory bowel diseases (IBD), are linked, directly or indirectly, to defects in the neural control of the Gl system. Neurogenic purines are central to gut motility by providing tonic inhibition in the colon and by influencing gut contractility and propulsion motility. In recent years we have determined that NAD+ and ADP-ribose, but not ATP, fulfill presynaptic and postsynaptic criteria for a motor inhibitory neurotransmitter in the colon. This project will build upon our findings and will pursue the mechanisms of release, metabolism and action of extracellular purines and metabolites with the goal to greatly improve our understanding of key mechanisms of purinergic signaling in the human gut.
In Aim 1 we will investigate key mechanisms of extracellular metabolism of ATP, NAD+ and ADPR, intersecting pathways, and regional prevalence of purinergic metabolic pathways in the large intestine.
In Aim 2 we will investigate the complexities of purinergic regulation in the colon and the postjunctional activities of purines and metabolites on muscle contractility and motility. In particular, we will investigate the involvment of P2X7 receptors and small conductance Ca2+-activated K-t- (SK) channels in PDGFRa+ cells in mediating responses to ATP and will examine purine-mediated Ca2+ desensitization mechanisms in colonic smooth muscle.
In Aim 3 we will investigate how neuronal release, degradation and action of extracellular purine nucleotides and metabolites are affected in colitis. We will conduct our studies on colons from human and non-human primates, in mice with specific gene deletions, in reporter strains of mice with constitutive expression of green fluorescence proteins, and in animal models of colitis. We will examine constitutive and evoked overflow and extracellular biotransformation of purines using enhanced high performance liquid chromatography techniques along with immunohistochemistry, protein biochemistry, fluorescence-activated cell sorting, electrophysiology, and functional approaches to better understand mechanisms of purinergic signaling in the gut. This research has the potential to advance new concepts in regulatory purine-mediated mechanisms in the distal Gl tract.

Public Health Relevance

Many Gl symptoms and motility disorders are linked to defects in the neural control of the Gl system. Inflammatory bowel disease (IBD) in particular (e.g. Crohn's disease and ulcerative colitis) accounts for a significant proportion of Gl disease and presents a significant economic healthcare burden in the U.S. and the developing worid. This project will greatly enhance knowledge of purinergic signaling in the gut and will likelv suggest novel strategies for preventing or correcting Gl diseases including IBD

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK041315-26
Application #
8742140
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J3))
Project Start
Project End
Budget Start
2014-08-20
Budget End
2015-07-31
Support Year
26
Fiscal Year
2014
Total Cost
$228,578
Indirect Cost
$69,290
Name
University of Nevada Reno
Department
Type
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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