CALCIUM DYNAMICS IN INTERSTITIAL CELLS OF CAJAL

Summary

Principal Investigator: Gianrico Farrugia
Abstract: DESCRIPTION (provided by applicant): The control of gastrointestinal (GI) motility requires a complex interaction between several cell types such as smooth muscle and enteric nerves. In recent years we have added interstitial cells of Cajal (ICC) to this complex system. ICC regulate smooth muscle function and loss of ICC is associated with several motility disorders. ICC networks are constantly turning over and maintenance of the networks requires tight regulation of ICC proliferation. Ano-1, a Ca2+ activated Cl- channel has recently been found to be selectively expressed on ICC in the muscle layers of the gut as well as in several tumors, including gastrointestinal stromal tumors. The overall objective of this proposal is to determine the role of Ano1 in ICC function. The central hypothesis of this proposal is that Ano-1 has dual, novel roles in ICC physiology. It acts as a key molecule in the regulation of ICC proliferation and as an ion channel required for the repolarization of the slow wave. The central hypothesis will be tested in two specific aims. Specific Aim 1 will test the hypothesis that Ano1 regulates proliferation of ICC and Specific aim 2 will test the hypothesis that Ano1 is required for repolarization of the slow wave. The first specific aim is supported by preliminary data that show that Ano1 in the tunica muscularis is expressed only on ICC, that Ano1 may be used to detect loss of ICC in motility disorders, that a lack of Ano1 is associated with a decrease in proliferation of ICC and that an increase in expression of Ano-1 is associated with an increase in ICC proliferation. The preliminary data also provide evidence, from bioinformatics analysis of microarray data comparing knockout to wild type mice, that key molecules associated with the control of proliferation, including CDK1/cdc2, are down-regulated when Ano1 is absent. The second specific aim is supported by preliminary data that show that Cl- channel blockers alter the duration of the plateau of the slow wave, that the slow wave is prolonged when Ano-1 expression is decreased and that it normalizes after Ano-1 is expressed. The PI will test the central hypothesis by a combination of innovative techniques including 3D reconstructions of immunohistochemical data, Western blots, RT-PCR, single cell PCR, quantitative PCR, lentivirus and si/shRNA knock down techniques, electroporation, knockout mice, organotypic and single cell cultures, bioinformatic analysis of microarray data, proteomics, Ca2+ and Cl- imaging, microelectrode recordings and patch clamp techniques. Successful completion of the proposed studies has both basic significance and clinical impact. Our work on the newly discovered protein Ano1 will provide mechanistic information on both how ICC networks are maintained and on the regulation of the slow wave. Of immediate clinical significance our work will inform clinicians and pathologists on use of antibodies to Ano1 to assess ICC in motility disorders and provide targets for future therapeutic interventions. Our work also has broad implications beyond the GI tract. As Ano-1 is expressed in many organs and tumors including gastrointestinal stromal tumors, our findings will likely apply to several other organs outside of the GI tract.
Funding Period: 2000-04-01 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Carbon monoxide, hydrogen sulfide, and nitric oxide as signaling molecules in the gastrointestinal tract
    Gianrico Farrugia
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota Electronic address
    Gastroenterology 147:303-13. 2014
  2. pmc A stochastic multi-scale model of electrical function in normal and depleted ICC networks
    Jerry Gao
    Auckland Bioengineering Institute, The University of Auckland, Auckland 1010, New Zealand
    IEEE Trans Biomed Eng 58:3451-5. 2011
  3. pmc Biophysically based modeling of the interstitial cells of cajal: current status and future perspectives
    Rachel Lees-Green
    Auckland Bioengineering Institute, The University of Auckland Auckland, New Zealand
    Front Physiol 2:29. 2011
  4. pmc Immunoreactivity for Ano1 detects depletion of Kit-positive interstitial cells of Cajal in patients with slow transit constipation
    P Kashyap
    Enteric NeuroScience Program and Department of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:760-5. 2011
  5. pmc Hydrogen sulfide is a partially redox-independent activator of the human jejunum Na+ channel, Nav1.5
    Peter R Strege
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
    Am J Physiol Gastrointest Liver Physiol 300:G1105-14. 2011
  6. pmc Gastrointestinal neuromuscular pathology in chronic constipation
    Charles H Knowles
    Neurogastroenterology Group, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK
    Best Pract Res Clin Gastroenterol 25:43-57. 2011
  7. pmc Altered expression of Ano1 variants in human diabetic gastroparesis
    Amelia Mazzone
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    J Biol Chem 286:13393-403. 2011
  8. pmc Cellular changes in diabetic and idiopathic gastroparesis
    Madhusudan Grover
    Mayo Clinic, Rochester, Minnesota, USA
    Gastroenterology 140:1575-85.e8. 2011
  9. pmc Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years
    Purna Kashyap
    Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
    Gut 59:1716-26. 2010
  10. pmc Changes in interstitial cells of cajal with age in the human stomach and colon
    P J Gomez-Pinilla
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:36-44. 2011

Research Grants

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  2. Strategies for Improved Shock Wave Lithotripsy
    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
  3. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
  4. Core Center for Musculoskeletal Disorders
    Louis J Soslowsky; Fiscal Year: 2013
  5. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  6. IBD and Mucosal Inflammation, Immunology, and Microbiology of the GI Tract
    Eugene B Chang; Fiscal Year: 2013
  7. Electrical control of gastric motility
    Kenton M Sanders; Fiscal Year: 2013
  8. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
  9. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
  10. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013

Detail Information

Publications62

  1. ncbi Carbon monoxide, hydrogen sulfide, and nitric oxide as signaling molecules in the gastrointestinal tract
    Gianrico Farrugia
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota Electronic address
    Gastroenterology 147:303-13. 2014
    ..We review their signaling functions in the luminal gastrointestinal tract and discuss how their pathways interact. We also describe other physiological functions of CO and H2S and how they might be used as therapeutic agents. ..
  2. pmc A stochastic multi-scale model of electrical function in normal and depleted ICC networks
    Jerry Gao
    Auckland Bioengineering Institute, The University of Auckland, Auckland 1010, New Zealand
    IEEE Trans Biomed Eng 58:3451-5. 2011
    ..The modified SNESIM algorithm can be used with simulation techniques to quantify the physiological consequences of ICC network depletion at various physical scales...
  3. pmc Biophysically based modeling of the interstitial cells of cajal: current status and future perspectives
    Rachel Lees-Green
    Auckland Bioengineering Institute, The University of Auckland Auckland, New Zealand
    Front Physiol 2:29. 2011
    ..The review concludes by examining several potential clinical applications of biophysically based ICC modeling from the subcellular through to the organ level, including ion channelopathies and ICC network degradation...
  4. pmc Immunoreactivity for Ano1 detects depletion of Kit-positive interstitial cells of Cajal in patients with slow transit constipation
    P Kashyap
    Enteric NeuroScience Program and Department of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:760-5. 2011
    ..Ano1 (DOG1 or TMEM16A) was recently described as a marker of ICC in GI tract. Our aim was to determine whether Ano1 immunoreactivity can be used as a reliable marker for ICC in tissues from patients with motility disorders...
  5. pmc Hydrogen sulfide is a partially redox-independent activator of the human jejunum Na+ channel, Nav1.5
    Peter R Strege
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
    Am J Physiol Gastrointest Liver Physiol 300:G1105-14. 2011
    ..5 peak current. These studies show that H(2)S activates the gastrointestinal Na(+) channel, and the mechanism of action of H(2)S is partially redox independent...
  6. pmc Gastrointestinal neuromuscular pathology in chronic constipation
    Charles H Knowles
    Neurogastroenterology Group, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK
    Best Pract Res Clin Gastroenterol 25:43-57. 2011
    ..Methods with practical diagnostic utility in the individual patient have rarely been employed and require further validation in respect of normative data...
  7. pmc Altered expression of Ano1 variants in human diabetic gastroparesis
    Amelia Mazzone
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    J Biol Chem 286:13393-403. 2011
    ..Changes in Ano1 expression in ICC may directly contribute to diabetic gastroparesis...
  8. pmc Cellular changes in diabetic and idiopathic gastroparesis
    Madhusudan Grover
    Mayo Clinic, Rochester, Minnesota, USA
    Gastroenterology 140:1575-85.e8. 2011
    ..Cellular changes associated with diabetic and idiopathic gastroparesis are not well described. The aim of this study was to describe histologic abnormalities in gastroparesis and compare findings in idiopathic versus diabetic gastroparesis...
  9. pmc Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years
    Purna Kashyap
    Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
    Gut 59:1716-26. 2010
    ..There is also a focus on advances in our understanding of the cellular changes that underlie development of diabetic gastroparesis, highlighting new opportunities for targeted treatment...
  10. pmc Changes in interstitial cells of cajal with age in the human stomach and colon
    P J Gomez-Pinilla
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:36-44. 2011
    ..The aim of this study was to determine the effect of aging on ICC number and volume in the human stomach and colon...
  11. pmc Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice
    Ferenc Izbeki
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Guggenheim 10, 200 1st Street SW, Rochester, MN 55906, USA
    J Physiol 588:3101-17. 2010
    ..Klotho protects ICC by preserving their precursors, limiting oxidative stress, and maintaining nutritional status and normal levels of trophic factors important for ICC differentiation...
  12. pmc Tissue-specific mathematical models of slow wave entrainment in wild-type and 5-HT(2B) knockout mice with altered interstitial cells of Cajal networks
    Peng Du
    Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
    Biophys J 98:1772-81. 2010
    ..This study provides a framework for evaluating how ICC network degradation may impair slow wave propagation and ultimately motility and transit...
  13. pmc Carbon monoxide reverses diabetic gastroparesis in NOD mice
    Purna C Kashyap
    Mayo Clinic, 200 First St SW, Rochester MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 298:G1013-9. 2010
    ..This effect of CO was independent of HO activity, suggesting that its effects were downstream of HO1. CO represents a potential therapeutic option for treatment of diabetic gastroparesis...
  14. pmc T-type Ca(2+) channel modulation by otilonium bromide
    Peter R Strege
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
    Am J Physiol Gastrointest Liver Physiol 298:G706-13. 2010
    ..This may represent a new mechanism of action for antispasmodics and may contribute to the observed increased clinical effectiveness of antispasmodics compared with selective L-type Ca(2+) channel blockers...
  15. pmc Ultrastructural differences between diabetic and idiopathic gastroparesis
    Maria Simonetta Faussone-Pellegrini
    University of Florence, Florence, Italy
    J Cell Mol Med 16:1573-81. 2012
    ..The significant differences found between diabetic and idiopathic gastroparesis offers insight into pathophysiology as well as into potential targeted therapies...
  16. pmc Ano1 as a regulator of proliferation
    Jennifer E Stanich
    Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
    Am J Physiol Gastrointest Liver Physiol 301:G1044-51. 2011
    ..These data led us to conclude that Ano1 regulates proliferation at the G(1)/S transition of the cell cycle and may play a role in tumorigenesis...
  17. pmc Quantification of gastrointestinal sodium channelopathy
    Yong Cheng Poh
    Division of Bioengineering, National University of Singapore, 9 Engineering Drive 1, Block EA 03 12 Singapore 117576, Singapore
    J Theor Biol 293:41-8. 2012
    ..Thus, the R76C mutation was sufficient to alter ICC and SMC cell electrophysiology. However, the cause-effect relationship between R76C and intestinal pseudo-obstruction remains an open question...
  18. pmc Computational modeling of anoctamin 1 calcium-activated chloride channels as pacemaker channels in interstitial cells of Cajal
    Rachel Lees-Green
    Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
    Am J Physiol Gastrointest Liver Physiol 306:G711-27. 2014
    ..The model shows that the Cl(-) equilibrium potential is an important modulator of slow wave morphology, highlighting the need for a better understanding of Cl(-) dynamics in ICC...
  19. pmc Non-canonical translation start sites in the TMEM16A chloride channel
    Elvira Sondo
    U O C Genetica Medica, Istituto Giannina Gaslini, Genova, Italy
    Biochim Biophys Acta 1838:89-97. 2014
    ..Future experiments will need to address the role of normal and alternative amino-terminus in TMEM16A structure and function. ..
  20. pmc Review article: carbon monoxide in gastrointestinal physiology and its potential in therapeutics
    S J Gibbons
    Enteric Neuroscience Program, Mayo Clinic, Rochester, MN 55905, USA
    Aliment Pharmacol Ther 38:689-702. 2013
    ..While carbon monoxide (CO) is a known toxin, it is now recognised that CO is also an important signalling molecule involved in physiology and pathophysiology...
  21. pmc Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties
    Jerry Gao
    Auckland Bioengineering Institute, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
    J R Soc Interface 10:20130421. 2013
    ..The metrics developed here enabled the first detailed quantitative analyses of structural changes that may occur in ICC networks during depletion and development. ..
  22. pmc Distribution of TMEM100 in the mouse and human gastrointestinal tract--a novel marker of enteric nerves
    S T Eisenman
    Enteric Neuroscience Program, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
    Neuroscience 240:117-28. 2013
    ..The expression of TMEM100 in the enteric nervous system may reflect a role in the development and differentiation of cells through a transforming growth factor β, BMP or related signaling pathway...
  23. pmc Kit signaling is required for development of coordinated motility patterns in zebrafish gastrointestinal tract
    Adam Rich
    Department of Biology, The College at Brockport, State University of New York, Brockport, NY 14420, USA
    Zebrafish 10:154-60. 2013
    ..These data suggest that Kit signaling is necessary for development of coordinated motility patterns and that Kit-positive cells in zebrafish are necessary for coordinated motility patterns...
  24. pmc Endoscopic full-thickness biopsy of the gastric wall with defect closure by using an endoscopic suturing device: survival porcine study
    Elizabeth Rajan
    Developmental Endoscopy Unit, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Gastrointest Endosc 76:1014-9. 2012
    ..Gastric wall biopsies that include the muscularis propria to evaluate the enteric nervous system, interstitial cells of Cajal, and immune cells can provide important insights for our understanding of the etiology of these disorders...
  25. pmc Inhibition of cell proliferation by a selective inhibitor of the Ca(2+)-activated Cl(-) channel, Ano1
    Amelia Mazzone
    Enteric Neuroscience Program, Mayo Clinic, Rochester, MN 55905, USA
    Biochem Biophys Res Commun 427:248-53. 2012
    ..Indeed, a role for Ano1 in regulating proliferation of tumors and ICC has been recently suggested. Recently, a high-throughput screen identified a small molecule, T16A(inh)-A01 as a specific inhibitor of Ano1...
  26. pmc Rapid high-amplitude circumferential slow wave propagation during normal gastric pacemaking and dysrhythmias
    G O'Grady
    Department of Surgery, The University of Auckland, Auckland, New Zealand
    Neurogastroenterol Motil 24:e299-312. 2012
    ....
  27. pmc Platelet-derived growth factor receptor α (PDGFRα)-expressing "fibroblast-like cells" in diabetic and idiopathic gastroparesis of humans
    M Grover
    Mayo Clinic, Rochester, MN, USA
    Neurogastroenterol Motil 24:844-52. 2012
    ..The aims of this study were to determine the morphology and distribution of PDGFRα-immunoreactive (ir) FLC in human gastric muscle and to determine if FLC are altered in gastroparesis, where ICC are reduced...
  28. pmc Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium
    M Grover
    Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 24:531-9, e249. 2012
    ..The association of these cellular changes with gastroparesis symptoms and gastric emptying is unknown. The aim of this study was to relate cellular changes to symptoms and gastric emptying in patients with gastroparesis...
  29. pmc Inhaled carbon monoxide attenuates myocardial inflammatory cytokine expression in a rat model of cardiopulmonary bypass
    Juan N Pulido
    Department of Anesthesiology, Mayo Clinic College of Medicine, Saint Mary s Hospital, Rochester, Minnesota 55905, USA
    J Extra Corpor Technol 43:137-43. 2011
    ..Further investigation in a survival model of CPB is warranted...
  30. pmc CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice
    Kyoung Moo Choi
    Enteric Neuroscience Program and Department of Physiology, Mayo Clinic, Rochester, Minnesota, USA
    Gastroenterology 138:2399-409, 2409.e1. 2010
    ..We investigated the number and phenotype of gastric macrophages in NOD/ShiLtJ (nonobese diabetic [NOD]) mice after onset of diabetes, when delayed gastric emptying develops, and after induction of HO1 to reverse delay...
  31. pmc Lack of serotonin 5-HT2B receptor alters proliferation and network volume of interstitial cells of Cajal in vivo
    V S Tharayil
    Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 22:462-9, e109-10. 2010
    ..The aims of this study were to investigate if adult ICC proliferate, whether the proliferation of ICC in vivo is affected by knocking out the 5-HT(2B) receptor, and if alterations in proliferation affect ICC networks...
  32. ncbi Distribution of interstitial cells of Cajal and nitrergic neurons in normal and diabetic human appendix
    S M Miller
    Division of Gastroenterology and Hepatology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 20:349-57. 2008
    ..The data also suggest that the human appendix, a readily available source of human tissue, may be useful model for the study of motility disorders...
  33. ncbi Evaluation of endoscopic approaches for deep gastric-muscle-wall biopsies: what works?
    Elizabeth Rajan
    Developmental Endoscopy Unit, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Gastrointest Endosc 67:297-303. 2008
    ....
  34. ncbi Evolving concepts in the cellular control of gastrointestinal motility: neurogastroenterology and enteric sciences
    Amelia Mazzone
    Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    Gastroenterol Clin North Am 36:499-513, vii. 2007
    ..The initial factors triggering these changes and how to intervene to prevent, halt, and reverse them needs to be understood...
  35. ncbi Determination of gastric emptying in nonobese diabetic mice
    Kyoung Moo Choi
    Enteric Neuroscience Program, Mayo Clinic College of Medicine, Rochester MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 293:G1039-45. 2007
    ..Opposing changes in gastric emptying between NOD LtJ and NOR LtJ mice suggest that NOR LtJ mice are not good controls for the study of gastric emptying in NOD LtJ mice...
  36. ncbi Exogenous serotonin regulates proliferation of interstitial cells of Cajal in mouse jejunum through 5-HT2B receptors
    Mira M Wouters
    Enteric Neuroscience Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Gastroenterology 133:897-906. 2007
    ..The mechanisms modulating ICC survival and proliferation are poorly understood. This study aimed to establish whether 5-hydroxytryptamine (5-HT) plays a role in regulating ICC proliferation...
  37. ncbi 5-HT receptors on interstitial cells of Cajal, smooth muscle and enteric nerves
    M M Wouters
    Enteric Neuroscience Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Neurogastroenterol Motil 19:5-12. 2007
    ..Despite the abundant expression of 5-HT(3) receptors in the human enteric nervous system no functional correlate has been as yet demonstrated...
  38. ncbi Regulation of interstitial cells of Cajal in the mouse gastric body by neuronal nitric oxide
    K M Choi
    Enteric Neuroscience Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Neurogastroenterol Motil 19:585-95. 2007
    ..Neuronally derived NO modulates ICC numbers and network volume in the mouse gastric body. NO appears to be a survival factor for ICC...
  39. ncbi Mechanosensitive ion channels in interstitial cells of Cajal and smooth muscle of the gastrointestinal tract
    R E Kraichely
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Neurogastroenterol Motil 19:245-52. 2007
    ..This has led to better comprehension of the role of mechanosensitive conductances in normal physiology and will undoubtedly lead to understanding of the consequences of disturbances in these conductances...
  40. ncbi Kit-like immunoreactivity in the zebrafish gastrointestinal tract reveals putative ICC
    A Rich
    Department of Biological Sciences, SUNY Brockport, Brockport, NY 14420, USA
    Dev Dyn 236:903-11. 2007
    ..Expression of kita and kitb, and the ligands kitla and kitlb, were verified in the adult GI tract. The anatomical arrangement of the Kit-positive cells strongly suggests that they are ICC...
  41. ncbi Species dependent expression of intestinal smooth muscle mechanosensitive sodium channels
    P R Strege
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Neurogastroenterol Motil 19:135-43. 2007
    ..These data show that there are species differences in expression of the SCN5A-encoded Na(v)1.5 channel, suggesting species-specific differences in the electrophysiological response to mechanical and depolarizing stimuli...
  42. ncbi Serotonergic modulation of murine fundic tone
    Lin Xue
    Enteric Neuroscience Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Am J Physiol Gastrointest Liver Physiol 291:G1180-6. 2006
    ..5-HT(3) receptors modulate excitatory neural input to murine fundic smooth muscle, and both 5-HT(3) and 5-HT(4) receptors modulate inhibitory neural input to murine fundic smooth muscle...
  43. ncbi Achalasia: physiology and etiopathogenesis
    R E Kraichely
    Enteric Neuroscience Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Dis Esophagus 19:213-23. 2006
    ....
  44. ncbi Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy
    G Richard Locke
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Am J Gastroenterol 101:1299-304. 2006
    ..The aim of this study was to determine if the cardiac channelopathy-associated mutations in SCN5A or KCNH2 are associated with GI symptom complexes...
  45. pmc Endoscopic "no hole" full-thickness biopsy of the stomach to detect myenteric ganglia
    Elizabeth Rajan
    Division of Gastroenterology and Hepatology, Developmental Endoscopy Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    Gastrointest Endosc 68:301-7. 2008
    ..A serious limitation to the technique was the resultant gastric wall perforation after tissue resection. The optimal procedure would seal the gastric wall defect before tissue resection, eliminating the risk of peritonitis...
  46. ncbi Interstitial cells of Cajal in health and disease
    G Farrugia
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 20:54-63. 2008
    ..This review will describe what is known about the function and role of ICC both in health and in a variety of motility disorders with a focus on unresolved issues pertaining to their role in the control of gastrointestinal motility...
  47. pmc A mutation in telethonin alters Nav1.5 function
    Amelia Mazzone
    Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota 55905, USA
    J Biol Chem 283:16537-44. 2008
    ..These results suggest a new role for telethonin, namely that telethonin is a sodium channel-interacting protein. Also, mutations in telethonin can alter Na(v)1.5 kinetics and may play a role in intestinal pseudo-obstruction...
  48. pmc Protein kinase C{gamma} mediates regulation of proliferation by the serotonin 5-hydroxytryptamine receptor 2B
    Mira M Wouters
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Rochester, Minnesota 55905, USA
    J Biol Chem 284:21177-84. 2009
    ..The data demonstrate that the 5-HT(2B) receptor-induced proliferative response of ICC is through phospholipase C, [Ca(2+)](i), and PKCgamma, implicating this PKC isoform in the regulation of cellular proliferation...
  49. pmc Neural autoantibody profile of primary achalasia
    Robert E Kraichely
    Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Dig Dis Sci 55:307-11. 2010
    ..5% in control subjects), in the absence of diabetes or companion antibodies predictive of type 1 diabetes. This profile of autoantibodies suggests an autoimmune basis for a subset of primary achalasia...
  50. pmc The alpha1H Ca2+ channel subunit is expressed in mouse jejunal interstitial cells of Cajal and myocytes
    Simon J Gibbons
    Enteric Neuroscience Program, Mayo Clinic College of Medicine, Rochester, MN, USA
    J Cell Mol Med 13:4422-31. 2009
    ..Furthermore, the survival of mice that do not express the alpha(1H) Ca(2+) channel protein is dependent on the genetic background and targeting approach used to generate the knockout mice...
  51. pmc Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract
    Pedro J Gomez-Pinilla
    Enteric Neuroscience Program, Miles and Shirley Fiterman Center for Digestive Diseases and Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 296:G1370-81. 2009
    ..Ano1 labels all classes of ICC and represents a highly specific marker for studying the distribution of ICC in mouse and human tissues with an advantage over Kit since it does not label mast cells...
  52. pmc Diagnostic challenges of motility disorders: optimal detection of CD117+ interstitial cells of Cajal
    Megan M Garrity
    Division of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USA
    Histopathology 54:286-94. 2009
    ..The aims of this study were therefore to determine the optimal protocol using FFPE tissue, determine normal values for ICC in non-neoplastic human colon, and compare results with those obtained using immunofluorescence (IF)...
  53. pmc Effect of age on the enteric nervous system of the human colon
    C E Bernard
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Neurogastroenterol Motil 21:746-e46. 2009
    ..This change was not accompanied by changes in total volume of neuronal structures suggesting compensatory changes in the remaining neurons...
  54. pmc Lysophosphatidyl choline modulates mechanosensitive L-type Ca2+ current in circular smooth muscle cells from human jejunum
    Robert E Kraichely
    Enteric Neuroscience Program, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 296:G833-9. 2009
    ..These findings suggest that changes in tension in the plasmalemmal membrane can be transmitted to the mechanosensitive L-type Ca2+ channel, leading to altered activity and Ca2+ entry in the human jejunal circular layer myocyte...
  55. pmc Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy
    Yuri A Saito
    Enteric Neuroscience Program, Miles and Shirley Fiterman Center for Digestive Disease, Mayo Clinic, Rochester, MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 296:G211-8. 2009
    ..In conclusion, the G298S-SCN5A missense mutation caused a marked reduction of whole cell Na(+) current and loss of function of Na(v)1.5, suggesting SCN5A as a candidate gene in the pathophysiology of IBS...
  56. pmc Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis
    Kyoung Moo Choi
    Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota 55905, USA
    Gastroenterology 135:2055-64, 2064.e1-2. 2008
    ..We proposed that Kit expression is lost during diabetic gastroparesis due to increased levels of oxidative stress caused by low levels of heme oxygenase-1 (HO-1), an important cytoprotective molecule against oxidative injury...
  57. pmc Apoptotic cell death of human interstitial cells of Cajal
    S J Gibbons
    Enteric Neuroscience Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Neurogastroenterol Motil 21:85-93. 2009
    ..Apoptotic cell death is a continuing process in ICC. The level of apoptosis in ICC in healthy colon indicates that these cells must be continually regenerated to maintain intact networks...
  58. pmc Changes in the gastric enteric nervous system and muscle: a case report on two patients with diabetic gastroparesis
    Pankaj J Pasricha
    Division of Gastroenterology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
    BMC Gastroenterol 8:21. 2008
    ..The aim of this study was to use modern analytical methods to determine morphological and molecular changes in the gastric wall in patients with diabetic gastroparesis...
  59. pmc Enteric autoantibodies and gut motility disorders
    Purna Kashyap
    Mayo Clinic, Rochester, MN 55905, USA
    Gastroenterol Clin North Am 37:397-410, vi-vii. 2008
    ..Algorithms are suggested for the work-up and treatment of patients with circulating antibodies associated with gastrointestinal motility disorders...
  60. pmc Effect of modulation of serotonergic, cholinergic, and nitrergic pathways on murine fundic size and compliance measured by ultrasonomicrometry
    Lin Xue
    Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 290:G74-82. 2006
    ..The data suggest that ultrasonomicrometry is a useful tool that can reproducibly and accurately measure changes in fundic size and the response to pharmacological agents...

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. Strategies for Improved Shock Wave Lithotripsy
    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
    ..and the session can be ended * Determine the mechanism by which cavitation within a vessel causes hemorrhage * Develop numerical models to understand the role of cavitation and non-cavitational mechanisms in causing tissue damage ..
  3. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
  4. Core Center for Musculoskeletal Disorders
    Louis J Soslowsky; Fiscal Year: 2013
    ..abstract_text> ..
  5. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  6. IBD and Mucosal Inflammation, Immunology, and Microbiology of the GI Tract
    Eugene B Chang; Fiscal Year: 2013
    ..Through its cost-effective, enabling technologies and services, the DDRCC has been a major factor in the advancement of scholarship and discovery in IBD and digestive diseases at the University of Chicago. ..
  7. Electrical control of gastric motility
    Kenton M Sanders; Fiscal Year: 2013
    ..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...
  8. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  9. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  10. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  11. Purinergic neurotransmission in the gut
    James J Galligan; Fiscal Year: 2013
    ..This information would help to develop new drug treatments for common motility disorders. ..
  12. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  13. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..