SPACE DPRuOnVwIDinErDn. Electrical pacemaker activity serves a critical function in gastric motility. Previous studies have determined that interstitial cells of Cajal (ICC), located in the myenteric region of the tunica muscularis of the corpus and antrum, are the primary pacemaker cells in- mammalian gastric muscles. Pacemaker events, originating near the greater curvature of the corpus, spread around and down the stomach to the pyloric sphincter.This activity, known as electrical slow waves, times the occurrence of gastric peristaltic contractions. Proper spread of slow waves depends upon a proximal-to-disjal gradient in the intrinsic frequency of pacemaker activity. Loss of pacemaker activity, emergence of ectopic pacemakers, or defects in slowwave propagation can lead to functional motility disorders of the stomach. This project seeks to understand the pacemaker mechanisms in gastric ICC;Studies will be performed on isolated ICC from the corpus arid antrum to determine the conductance(s) responsible for pacemaker currents and the intracellular events leading.to activation of pacemaker currents. We have found that the gastric pacemaker frequency gradient is encoded in ICC from the corpus and antrum, and further experiments will dissect the differences in pacemaker activity of the ICC from these regions to understand the basis for the pacemakerfrequency gradient. We will also determine whether the mechanisms responsible for generation of pacemaker current are required for regeneration of slow waves, and experiments will be performed to understand how electrical pacing from an external current source can affect generation and propagation of slow waves. Experiments to determine the factors involved in regulation of pacemaker .frequency in ICC and to determine the mechanisms, by which various biogenic chemicals affect the timing of .pacemaker events will be performed. This information may provide new insights into the causes (and perhaps cures) for gastric arrhythmias. Basic information about generation, propagation and regulation of pacemaker frequency will be upounded in studies of intact muscles to explore the nature of the gastric'frequency gradient and ho y changes in pacemaker frequency affect the spread of slow waves (i.e. functional coupling) between the corpus and antrum.. New animal models of gastric arrhythmias will be studied to determine how pacemaker abnormalities affect functional coupling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK040569-23
Application #
8208151
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hamilton, Frank A
Project Start
1988-08-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
23
Fiscal Year
2012
Total Cost
$344,260
Indirect Cost
$99,235
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
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
Sanders, Kenton M; Ward, Sean M; Koh, Sang Don (2014) Interstitial cells: regulators of smooth muscle function. Physiol Rev 94:859-907
Zhu, Mei Hong; Sung, In Kyung; Zheng, Haifeng et al. (2011) Muscarinic activation of Ca2+-activated Cl- current in interstitial cells of Cajal. J Physiol 589:4565-82
Bayguinov, O; Hennig, G W; Sanders, K M (2011) Movement based artifacts may contaminate extracellular electrical recordings from GI muscles. Neurogastroenterol Motil 23:1029-42, e498
Rhee, Poong-Lyul; Lee, Ji Yeon; Son, Hee Jung et al. (2011) Analysis of pacemaker activity in the human stomach. J Physiol 589:6105-18
Ro, Seungil; Park, Chanjae; Jin, Jingling et al. (2010) A model to study the phenotypic changes of interstitial cells of Cajal in gastrointestinal diseases. Gastroenterology 138:1068-78.e1-2
Zhu, Mei Hong; Kim, Tae Wan; Ro, Seungil et al. (2009) A Ca(2+)-activated Cl(-) conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity. J Physiol 587:4905-18
Forrest, Abigail S; Hennig, Grant W; Jokela-Willis, Sari et al. (2009) Prostaglandin regulation of gastric slow waves and peristalsis. Am J Physiol Gastrointest Liver Physiol 296:G1180-90
McCloskey, K D; Anderson, U A; Davidson, R A et al. (2009) Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild-type and W/Wv mice. Br J Pharmacol 156:273-83
Faville, R A; Pullan, A J; Sanders, K M et al. (2009) Biophysically based mathematical modeling of interstitial cells of Cajal slow wave activity generated from a discrete unitary potential basis. Biophys J 96:4834-52

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