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Seán M. Ward, Ph. D.Professor
My laboratory is interested in the mechanisms underlying rhythmicity and neuroeffector transmission in visceral organs. Over the last decade we have developed a multi-faceted approach to understand the cell types responsible for the generation of pacemaker activity that leads to phasic contractions of many visceral tissues, especially those of the gastrointestinal tract. We have also increased our understanding of how motor nerve terminals communicate with smooth muscle cells in visceral tissues. Morphological, electrophysiological, molecular biological approaches and calcium imaging including the use of several mutant animal models that have disrupted Kit signaling have led us to the conclusions that there are specialized cells within the walls of visceral organs, called Interstitial cells of Cajal (ICCs). It is now clear that ICCs serve as: (i) pacemaker cells, generating the spontaneous electrical rhythms within the gastrointestinal tract known as slow waves; (ii) a propagation pathway for slow waves in GI muscles so that large areas of the musculature can be entrained to a dominant pacemaker frequency; (iii) mediators of excitatory cholinergic and inhibitory nitrergic neural inputs from the enteric nervous system, and (iv) stretch receptors that modulate membrane potential and electrical slow wave frequency in gastrointestinal muscles. Examples of different populations of ICC that exist within the GI tract are illustrated in the digital reconstructions of confocal images illustrated below. The loss of ICC that lie within the intermuscular plane of the small intestine (see confocal image on left) leads to a disruption in pacemaker activity and propagation of slow waves in the small intestine. An absence of intramuscular interstitial cells in the stomach (see image on right) leads to a loss of cholinergic and nitrergic neurotransmission of the stomach wall as well as a loss of stretch-dependent responses in the gastric musculature.
The collegial environment within the Department of Physiology
and Cell Biology has allowed members of my laboratory to develop
ongoing collaborations with many faculty within our Department
and other Departments at the University Of Nevada School Of Medicine.
These collaborations have led to the multifaceted approach that
we have applied to visceral tissues and our rapid understanding
of the functional roles of these cells within the gastrointestinal
tract and other organs.
Panel A Panel B Search For Dr. Ward's Publications In PubMed Ward, S.M., Beckett, E.A.H., Wang, X-Y., Baker, F., Khoyi, M. and Sanders, K. M. Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons. Journal of Neuroscience.20 (4): 1393-1403, 2000. Sanders, K. M., Ordog, T., Koh, S. D. and Ward, S. M. A Novel pacemaking mechanism drives gastrointestinal rhythmicity. News in Physiological Sciences 15: 291-298, 2000. Ward, S.M. Interstitial cells of Cajal in enteric neurotransmission. Gut. 2000 4:40-43, 2000. Ward, S. M. Role of interstitial cells of Cajal in gastric motility and neuromuscular dysfunctions. In Evolving Pathophysiological Models of Functional GI Disorders. Implications for drug development. Primary peripheral pathophysiological models within the gastrointestinal tract. pp 30-34, 2000. Stratton, C. J., Bayguinov, Y., Sanders, K. M. and Ward, S. M. Ultrastructural analysis of the transdifferentiation of smooth muscle to skeletal muscle in the murine esophagus. Cell and Tissue Research. 301(2): 283-298, 2000. Ward, S.M., Ordog, T., Koh, S. D., Baker, A Abu, Jun J. Y., Amberg, G., Monaghan, K. and Sanders K.M. Pacemaking mechanism driven by a mitochondrial clock. Journal of Physiology 525: 355-361, 2000. Ordog, T., Takayama, I., Cheung, W. K. T., Ward, S.M. and Sanders, K.M. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes, 49: 1731-1739, 2000. Epperson, A., Hatton, W. J., Callaghan, B., Walker, R., Sanders, K. M., Ward, S.M. and Horowitz, B. Molecular components expressed in cultured and freshly isolated interstitial cells of Cajal. American Journal of Physiology, 279: C529-C539, 2000. Smyth, L., Bobalova, J., Ward, S. M. and Mutafova-Yambolieva, V. N. Neuropeptide Y is a cotransmitter with norepinephrine in guinea pig inferior mesenteric vein. Peptides 21: 835-843, 2000. Wang, X-Y., Sanders, K. M. and Ward, S.M. Relationship between and interstitial cells of Cajal and enteric motor neurons in the murine proximal colon. Cell and Tissue Research.302, 331-342, 2000. Koh S. D., Kim, T. W., Jun, J. Y., Glasgow, N. J., Ward, S, M. and Sanders, K. M. Regulation of pacemaker currents in interstitial cells of Cajal by cyclic nucleotides. Journal of Physiology 527.1: 149-162, 2000. Ward, S. M. and Kenyon, J. L. The spatial relationships between Ca2+ channels and Ca2+ -activated channels and the function of Ca2+ -buffering in avian sensory neurons. Cell Calcium. 28:233-246, 2000. Smyth, L., Bobalova, J., Ward, S.M., Keef, K.D. and Mutafova-Yambolieva, V.N. Cotransmission from sympathetic vasoconstrictor neurons: differences in guinea-pig mesenteric artery and vein. Autonomic Neuroscience: Basic and Clinical 86: 1829, 2000. Jun JY, Kong ID, Koh SD, Wang XY, Perrino BA, Ward SM, Sanders KM. Regulation of ATP-sensitive K(+) channels by protein kinase C in murine colonic myocytes. Am J Physiol Cell Physiol. 281: C857-C864, 2001. Takeda, M., Takayama, I., Terada, N., Baba, T., Ward, S. M., Ohno, S. and Fujino, M. A. Immunoelectron-microscopic study of Kit-expressing cells in the jejunum of wildtype and Ws/Ws rats. Cell and Tissue Research 304: 21-30, 2001. Takayama, I., Daigo, Y., Ward, S. M. Sanders, K. M., Yamanaka, T. and Fujino, M. Differential gene expression in the small intestines of wildtype and W/W(V) mice. Neurogastroenterology and Motility13:163-168, 2001. Ward, S. M. and Sanders K. M. Interstitial cells of Cajal: Primary targets of enteric motor innervation. The Anatomical Record 262: 125-135, 2001. Patterson, L. M. Huiyuan Zheng, Ward, S. M. and H -R Berthoud. Immunohistochemical identification of CCKA-receptors on interstitial cells of Cajal, smooth muscle, and enteric neurons in rat pylorus. Cell and Tissue Research 305: 11-23, 2001. Chang, I-Y., Glasgow, N. J., Takayama, I., Horiguchi, K., Sanders, K. M. and Ward, S. M. Loss of interstitial cells of Cajal and development of electrical dysfunction in murine small bowel obstruction. J. Physiol. 536: 555-568, 2001. Horiguchi, K., Semple, G. S. A., Sanders, K. M and Ward, S. M. Distribution of pacemaker function through the tunica muscularis of the canine gastric antrum. J. Physiol. 537:237-250, 2001. Ward, S.M. and Sanders, K. M. Physiology and pathophysiology of the interstitial cell of Cajal: from bench to bedside. III. I. Functional development and plasticity of interstitial cells of Cajal networks. American Journal of Physiology 281: G602-G611, 2001. Sanders, K. M., Ordög, T and Ward, S.M. Physiology and pathophysiology of the interstitial cell of Cajal: from bench to bedside. III. Genetic and animal models for studying motor dysfunction resulting from defects in interstitial cells of Cajal. American Journal of Physiology 282: G747-G756, 2002. Takayama, I., Daigo, Y., Ward, S. M. Sanders, K. M., Yamanaka, T. and Fujino, M. Novel Human and Mouse Genes Encoding an Acid Phosphatase Family Member and Its Down-Regulation in W/WV Mouse Jejunum. Gut 50:790-796, 2002. Kim, T. W., Beckett, E. A.H., Hanna, R., Koh, S. D. Ordog, T., Ward S. M. and Sanders, K. M. Regulation of pacemaker currents in interstitial cells of Cajal by cyclic nucleotides. J. Physiol. 538.1: 145-157, 2002. Porcher, C., Baldo, M., Henry, M., Orsoni, P., Julé, Y. and Ward, S. M. Deficiency of Interstitial Cells of Cajal in the Small Intestine of Patients with Crohn’s Disease. American Journal of Gastroenterology 97: 118-125, 2002. Keef, K., Ward, S. M. and Sanders,K. M. Electrical activity in the canine rectal region. American Journal of Physiology 282: G123-G129, 2002 Hirst, G.D.S., Beckett, E.A.H., Sanders, K. M. and Ward, S. M. Regional variation in contribution of myenteric and intramuscular interstitial cells of Cajal to generation of slow waves in mouse gastric antrum. Journal of Physiology 540: 1003-1012, 2002. Porcher, C., Horowitz, B., Bayguinov, O., Ward, S. M. and Sanders, K. M. Constitutive expression and function of cyclooxygenase II in murine gastric muscles. Gastroenterology 122: 1442-1454, 2002. Sanders, K. M., Ward, S. M. and Daniel E. E. Role of intramuscular interstitial cells of Cajal in the gastrointestinal tract. ICC in neurotransmission: hard to swallow a lack of involvement. Gastroenterology, 122: 1185-1186, 2002. Ward, S. M., Gershon, M. D., Bayguinov, J. R., Nelson, C., Keef, K. and Sanders,K. M. Distribution of ICC and electrical activity in the large intestine “ganglionic and aganglionic regions” of ls/ls mutant mice. American Journal of Physiology 283: G445-G456, 2002. Sergeant, G. P., Large, R. J., Beckett, E.A.H, Mc Geough, C. M., Ward, S. M. and Horowitz, B. Microarray comparison of normal and W/Wv mice in the gastric fundus indicates a supersensitive phenotype. Physiological Genomics 11: 1-9, 2002. Beckett, E. A. H. Horiguchi, K., Khoyi, M., Sanders, K. M. and Ward, S.M. Interstitial cells of Cajal transduce enteric motor neurotransmission in the murine gastric fundus. Journal of Physiology. 543: 871-887, 2002.
McCloskey, K. D., Hollywood, M. A., Thornbury, K. D., Ward,
S. M. and N. G. McHale
Yamboliev, I. A., Ward, S. M. and Mutafova-Yambolieva,
V. N. Contractile protein Suzuki, H., Ward, S.M., Bayguinov, Y.R., Edwards, F. and Hirst G. D. S. Involvement in intramuscular interstitial cells of Cajal in nitrergic inhibition in the mouse gastric antrum. Journal of Physiology. 546:751-763, 2003. Kim, T. W., Koh, S. D., Ördög , T. Ward, S. M. and Sanders, K. M. Muscarinic regulation of pacemaker frequency in gastric interstitial cells of Cajal. Journal of Physiology 546: 415-425, 2003. Horiguchi, K., Keef, K. and Ward, S. M. Distribution of interstitial cells of Cajal in the tunica muscularis of the canine recto-anal region. American Journal of Physiology (GI and Liver), 284: G756-G767, 2003. Mutafova-Yambolieva, V. N., O’Driscoll, K., Farrelly, A., Ward, S. M. Keef, K. D. Spatial localization and properties of pacemaker potentials in the canine rectoanal region. American Journal of Physiology (GI and Liver), 284: G748-G755, 2003. Horiguchi, K., Sanders, K. M. and Ward, S. M. Enteric motor neurons form synaptic-like junctions with interstitial cells of Cajal in the canine gastric antrum. Cell and Tissue Research. 311: 299-313, 2003. Ward, S. M. and Sanders, K. M. Interstitial cells of Cajal. Encyclopedia of Gastroenterology. Elsevier (USA), pp 439-442, 2004. Ward, S. M., Baker, S. de Faoite, A. and Sanders, K. M. Propagation of slow waves requires regeneration via IP3 receptors and mitochondrial ca2+ uptake mechanism in canine colonic muscles. Journal of Physiology. 549: 207-218, 2003. Patterson, L. M., Zheng, H., Ward, S. M. and Berthoud, H. R. Vanilloid receptor (VR1)-expression in vagal afferent neurons innervating the gastrointestinal tract. Cell and Tissue Research 311: 277-287, 2003. Ward, S. M., Bayguinov, Y., Berthoud, H. R. and Grundy, D. Distribution of the vanilloid receptor (VR1) in the gastrointestinal tract. Journal of Comparative Neurology. 465: 121-135, 2003. Wang XY, Ward, S. M., Gerthoffer, W.T. and Sanders, K. M. Protein kinase C? translocation in enteric neurons and interstitial cells of Cajal in response to muscarinic stimulation. American Journal of Physiology. 285: G593 - G601, 2003. Campbell, J.D., Ward, S.M., Rich, A. and Sanders, K.M. Effects of haloperidol on voltage dependent currents and electrical slow waves in canine colonic muscle. Under review.
Takayama, I, Ward, S. M., Sanders, K. M., Fujino, M. A. and Ohno, S. Ultrastructure of enteric neurons in murine jejunum by in vivo cryotechnique. Under review. Daigo, Y., Takayama, I., Ponder, B. A. J., Caldas, C., Ward, S. M., Sanders K. M., Fujino, M. A. Differential gene expression profile in the small intestines of mice lacking pacemaker interstitial cells of Cajal. BMC Gastroenterology. 3: 17, 2003. Daigo, Y., Takayama, I., Ward, S. M., Sanders, K. M. and Fujino, M. A. Differential gene expression in the murine gastric fundus lacking interstitial cells of Cajal. BMC Gastroenterology 3:14, 2003. Beckett, E.A.H., Mc Geough, C. A., Sanders, K. M. and Ward, S.M. Pacing of interstitial cells of Cajal in the murine gastric antrum: neurally mediated and direct stimulation. Journal of Physiology. 553: 545-559, 2003. Daigo, Y., Takayama, I., Ward, S.M., Sanders, K.M. and Fujino, M.A. Novel human and mouse genes encoding a shank-interacting protein and its upregulation in gastric fundus of W/WV mouse. Journal of Gastroenterology and Hepatology. 18: 712-718, 2003. Koh, S.D., Ward, S.M., Ordog, T., Sanders, K.M. and Horowitz B. Conductances responsible for slow wave generation and propagation in interstitial cells of Cajal. Current Opinions in Pharmacology. 3:579-582, 2003. Hirst, G. D. S. and Ward, S. M. Interstitial cells, involvement in rhythmicity and neural control of smooth muscle cells. Journal of Physiology 550: 337-346, 2003. Sanders, K. M., Koh, S. D., Ordog T., and Ward, S. M. Ionic conductances involved in generation and propagation of electrical slow waves in phasic gastrointestinal muscles. Neurogastroenterology and Motility Suppl 1: 100-105, 2004. Ward, S. M., Sanders, K. M. and Hirst GDS. Hirst. Role of interstitial cells of Cajal in neural control of gastrointestinal smooth muscles. Neurogastroenterology and Motility Suppl 1: 107-112, 2004. Ozaki, H., Kawai, T., Won, K-J, Suzuki, T, Sato K., Horiguchi, K., Hori, M, Karaki, H., Torihashi, S., Ward, S. M., and Sanders, K. M. Isolation and characterization of resident macrophages from the smooth muscle layers of murine small intestine. Neurogastroenterology and Motility. 16: 39-51, 2004 Porcher, C., Horowitz, B.,Ward, S. M. and K.M. Sanders. Constitutive and functional expression of cyclooxygenase II in the murine proximal colon. Neurogastroenterology and Motility 16: 785-799, 2004. Iino, S., Ward, S. M. and Sanders, K. M. Interstitial cells of Cajal are functionally innervated by excitatory motor neurons in the murine intestine. Journal of Physiology, 556: 521-530, 2004. Hennig, G.W., Hirst, G.D.S., Park, K. J., Smith, C. B., Sanders, K. M., Ward, S. M., Smith, T. K. Propagation of pacemaker activity in the guinea-pig antrum. Journal of Physiology, 556:585-599, 2004. Daigo, Y., Takayama, I., Ponder, B.A., Caldas, C., Ward, S.M., Sanders, K.M., Fujino, M.A. Novel human, mouse and xenopus genes encoding a member of the RAS superfamily of low-molecular-weight GTP-binding proteins and its downregulation in W/WV mouse jejunum. Journal of Gastroenterololgy and Hepatology, 19: 211-217, 2004. Daigo Y, Takayama I, Ward SM, Sanders KM, Fujino MA. Isolation of novel mouse genes that were differentially expressed in W/W(V) mouse fundus. Journal of Gastroenterology 39:238-241, 2004. Beckett, E.A.H., Bayguinov, Y. R., Sanders, K. M., Ward, S. M. Properties of unitary potentials generated by intramuscular interstitial cells of Cajal in the murine and guinea-pig gastric fundus. Journal of Physiology, 559: 259-269, 2004. Yanagida, H., Yanase, H., Sanders, K. M. and Ward, S. M. Intestinal surgical resection disrupts electrical rhythmicity neural responses and ICC networks. Gastroenterology, 127(6):1748-1759, 2004. Suzuki, T., Won, K-J., Horiguchi, K., Kinoshita, K., Hori, M., Torihashi, S., Momotani, E., Ito, K., Hirayama, K., Ward, S. M., Sanders, K. M. and Ozaki, H. Muscularis inflammation and the loss of interstitial cells of Cajal in the endothelin ETB receptor null rat. American Journal of Physiology. 287:G638-G646, 2004. Ward, S. M., Dixon, R., deFaoite A., Sanders, K. M. Voltage dependent mechanism underlies entrainment and propagation of slow waves in canine gastric antrum. Journal of Physiology, 561: 793-810, 2004. Sanders, K. M., Ordog, T., Koh, S. D. and Ward, S.M. Properties of electrical rhythmicity in the stomach. In Handbook of Electrogastrography. Eds: K. L. Koh and R. M. Stern. Oxford University Press Inc. 2004. Sanders, K. M., Koh, S.D. and Ward S. M. Organization and Electrophysiology of Interstitial Cells of Cajal and Smooth Muscle Cells in the Gastrointestinal Tract. In Physiology of The Gastrointestinal Tract. Edited by Leonard R. Johnson., 2005. Takeda, Y., Ward, S. M., Sanders, K. M. and Koh, S. D. Effects of the gap junctional blocker glycyrrhetinic acid on ionic currents of gastrointestinal smooth muscle cells. American Journal of Physiology, 288:G832-G841, 2005. Won, K-J, Sanders, K. M. and Ward, S. M. Stretch induced changes in pacemaker frequency are mediated through ICC in the murine gastric antrum. Proceedings of the National Academy of Science, 102: 14913-14918, 2005. Beckett, EAH., Takeda, Y., Sanders, K. M. and Ward, S. M. Synaptic specializations exist between enteric motor nerves and interstitial cells of Cajal in the murine stomach. Journal of Comparative Neurology, 493: 193-206, 2005. Song G., Hirst G.D.S., Sanders, K. M. and Ward S. M. Regional variation in ICC distribution, pacemaking activity and neural responses in the longitudinal muscle of the murine stomach. Journal of Physiology, 564: 523-540, 2005. Cho, S. Y., Beckett, E. A., Baker, S. A., Han, I., Park, K. J., Monaghan, K., Ward, S.M., Sanders, K. M. and Koh, S. D. A pH-sensitive potassium conductance (TASK) and its function in the murine gastrointestinal tract. Journal of Physiology, 565:243-259, 2005. Park, K.J., Hennig, G.W., Lee, H.T., Spencer, N.J., Ward, S.M., Smith, T.K. and Sanders, K.M. Spatial and temporal mapping of pacemaker activity in interstitial cells of Cajal in mouse ileum in situ. American Journal of Physiology; Cell Physiol. 290:C1411-C1427, 2006. Ward, S.M., McLaren, G. J. and Sanders, K. M. Interstitial cells of Cajal in the deep muscular plexus mediate enteric motor transmission in the small intestine. Journal of Physiology. 573:147-159, 2006 Song G., Dixon, R,Beckett, E.A.H., Sanders, K. M. and Ward S. M. Excitatory neurokinin responses are intact in the stomach in the absence of ICC-IM. Under review. Hwang, S-J., Sanders, K. M and Ward, S. M. Evidence for the functional role of P2Y1 and P2Y4 receptors in the purinergic component of the inhibitory junction potential in the murine colon. Under review. Iino, S., Horiguchi, K., Ito, T., Nojyo, Y., Ward, S.M. and Sanders, K. M. Interstitial cells of Cajal contain signaling molecules for transduction of nitrergic stimulation in guinea pig cecum. Under Review. Stratton, C. J., Horiguchi, K., Sanders, K. M and Ward, S. M. Immunocytochemical identification of interstitial cells of Cajal in the murine fundus using a live-labeling technique. Neurogastroenterology and Motility, 2006, In press. Beckett, Sanders and Ward, S. M. Development of interstitial cells of Cajal requires signaling from the Kit receptor prior to and after birth. Developmental Dynamics, In Press. Sanders, K.M. and Ward, S.M. Interstitial cells of Cajal - a new perspective on smooth muscle function. Journal of Physiology. 576:675-682, 2006. McHale, N,G,, Hollywood, M.A., Sergeant, G.P., Thornbury, K.D., Shafei, M. and Ward, S.M. Organization and function of ICC in the urinary tract. Journal of Physiology. 576: 689-694, 2006. Chen, H., Redelman, D., Ro, S., Ward, S.M., Ordog, T. and Sanders, K.M..Selective labeling and isolation of functional classes of interstitial cells of.Cajal of the human and murine small intestine. American Journal of Physiology, Cell Physiology, 2006 Aug 30; [Epub ahead of print] Sanders, K.M. Koh, S.D and Ward, S. M. Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Annual Review of Physiology. 68:307-343, 2006. Ward, S. M. and Sanders, K. M. Involvement of intramuscular ICC in neuroeffector transmission in the gastrointestinal tract. Journal of Physiology. 576:675-82, 2006. Lavoie, B., Balemba, O.B., Nelson, M. T., Ward, S.M. and Mawe, G. M. Morphological and Physiological evidence for interstitial cell of Cajal (ICC)-like cells in the guinea pig gallbladder. Journal of Physiology. In Press.
Sanders, K.M., Koh, S.D., Ward, S. M. Interstitial
Cells of Cajal as pacemakers and mediators of enteric motor transmission.
Handbook of Physiology. In Press
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