Interstitial Cells of Cajal in Diabetic Gastropathy
Principal Investigator: TAMAS ORDOG
Abstract: DESCRIPTION (provided by applicant): Somatic stem cells residing in many organs are responsible for tissue maintenance and repair and also contribute to aging and cancer. While the role of stem cells and cell turnover is obvious in rapidly renewing tissues, their significance in the gastrointestinal neuromuscular compartment has only recently been recognized. The classic view of gastrointestinal motility disorders including diabetic gastroparesis is that they are due to impaired tissue function and degeneration of terminally differentiated cell types such as enteric neurons, smooth muscle cells and interstitial cells of Cajal (ICC). This is also reflected in current treatment modalities, which focus on symptom control and stimulation of residual function. However, these treatments are not curative and to a large extent ineffective. Recent studies demonstrating considerable plasticity of postnatal enteric neurons, smooth muscle cells and ICC indicate that this old view is untenable. We recently identified a stem cell residing in the gastric musculature of adult mice that can give rise to ICC (ICC-SC). This paradigm shift has opened entirely new opportunities to unravel the mechanisms of ICC maintenance and differentiation and to develop new, rational therapies to regenerate ICC networks from endogenous or transplanted tissue stem cells in these disorders. However, there are several barriers that must be overcome before this goal can be realized including a lack of understanding of the mechanisms that control ICC-SC self- renewal and differentiation, as well as the role of the tissue microenvironment in these processes. Therefore, the overall goals of the current project are to determine the key cell-intrinsic and cell-extrinsic factors that control ICC-SC proliferation and differentiation and to test pharmacological agents that target ICC-SC via these factors in preclinical disease models. Our first specific aim is to determine the role and mechanisms-of-action of polycomb group proteins as cell-intrinsic factors in the epigenetic control of ICC-SC maintenance and differentiation and to test the in vivo utility of indirect histone methyltransferase inhibitors to stimulate, through the inhibition of polycomb activity, the differentiation of transplanted and endogenous ICC-SC. Our second specific aim is to determine the role and molecular mechanisms-of-action of glycogen synthase kinase 3 (Gsk3) as an extrinsic factor in regulating ICC-SC through stem cell factor expression in smooth muscle cells and to determine the in vivo utility of Gsk3 inhibitors to reverse gastroparesis by supporting ICC-SC self- renewal and differentiation. We will use novel models and new technology developed in our laboratory including freshly isolated and cultured ICC-SC, transplantation of genetically labeled ICC-SC, and quantitative analysis of key stages of ICC development by flow cytometry. We will also employ state-of-the-art molecular biological and recombinant DNA techniques to study epigenetic control of gene transcription and mouse models for preclinical testing. The proposed studies will determine the mechanistic basis for, and set the stage for clinical trials of, novel pharmacological interventions for loss of ICC in motility diseases.
Funding Period: 2000-07-01 - 2016-07-31
more information: NIH RePORT
- Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesisViktor J Horváth
Department of Physiology and Cell Biology, University of Nevada, Reno, Nevada, USA
Gastroenterology 130:759-70. 2006..Most murine gastric ICC depend on stem cell factor (SCF) signaling but can also be maintained with insulin or insulin-like growth factor-I (IGF-I). We investigated whether SCF could mediate the actions of insulin and IGF-I...
- Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathwaysYujiro Hayashi
Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
PLoS ONE 8:e76822. 2013....
- Epigenetics and chromatin dynamics: a review and a paradigm for functional disordersT Ordog
Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Neurogastroenterol Motil 24:1054-68. 2012....
- Ano1 as a regulator of proliferationJennifer 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...
- Generalized neuromuscular hypoplasia, reduced smooth muscle myosin and altered gut motility in the klotho model of premature agingD T Asuzu
Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55906, USA
Neurogastroenterol Motil 23:e309-23. 2011..We also detected reduced fecal output in these animals; therefore, the aim of this study was to investigate in vivo function and cellular make-up of the small intestinal and colonic neuromuscular apparatus...
- Polycomb and the emerging epigenetics of pancreatic cancerAdrienne Grzenda
Laboratory of Chromatin Dynamics and Epigenetics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
J Gastrointest Cancer 42:100-11. 2011..Disruption of chromatin organization can directly and indirectly precipitate genomic instability and transformation...
- Changes in interstitial cells of cajal with age in the human stomach and colonP 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...
- Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumorsMichael R Bardsley
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
Gastroenterology 139:942-52. 2010..In mouse models we investigated whether Kit(low) ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST...
- Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric miceFerenc 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...
- Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meetingH P Parkman
Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
Neurogastroenterol Motil 22:113-33. 2010..Similarly, the diagnostic and treatment options for these two disorders are relatively limited despite recent advances in our understanding of both disorders...
- Cellular pathogenesis of diabetic gastroenteropathyT Ordog
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
Minerva Gastroenterol Dietol 55:315-43. 2009..Future research should identify ways to block cytotoxic factors, support the regeneration of damaged cells and translate the experimental findings into new treatment modalities...
- Review article: gastric electrical stimulation for gastroparesis--physiological foundations, technical aspects and clinical implicationsE Soffer
Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
Aliment Pharmacol Ther 30:681-94. 2009..Most studies focused on the use of electrical stimulation for gastroparesis, the only approved indication for such intervention...
- Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tractPedro 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...
- Progenitors of interstitial cells of cajal in the postnatal murine stomachAndrea Lorincz
Department of Physiology and Cell Biology, University of Nevada, Reno, USA
Gastroenterology 134:1083-93. 2008..Our goal was to identify ICC precursors in postnatal murine gastric muscles...
- Do we need to revise the role of interstitial cells of Cajal in gastrointestinal motility?TAMAS ORDOG
Am J Physiol Gastrointest Liver Physiol 294:G368-71. 2008
- Interstitial cells of Cajal in diabetic gastroenteropathyT Ordog
Department of Physiology and Biomedical Engineering, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
Neurogastroenterol Motil 20:8-18. 2008..Future research should focus on the identification of the molecular and cellular mechanisms underlying ICC loss in diabetes and the translation of the experimental findings into treatments...
- Differential gene expression in functional classes of interstitial cells of Cajal in murine small intestineHui Chen
Department of Physiology and Cell Biology, University of Nevada, School of Medicine, Reno, NV 89557, USA
Physiol Genomics 31:492-509. 2007..Our results may lead to the identification of novel biomarkers for ICC and provide directions for further studies designed to understand ICC function in health and disease...
- Selective labeling and isolation of functional classes of interstitial cells of Cajal of human and murine small intestineHui Chen
Department of Physiology and Cell Biology, School of Medicine, University of Nevada Reno, Reno, NV 89557, USA
Am J Physiol Cell Physiol 292:C497-507. 2007..ICC-DMP express neurotransmitter receptors and signaling intermediate molecules that are consistent with their role in neuromuscular neurotransmission...
- Dystrophin is a tumor suppressor in human cancers with myogenic programsYuexiang Wang
Department of Pathology, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
Nat Genet 46:601-6. 2014..These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in the treatment of cancer...
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- Regulating fibrosis and muscle growth in the muscular dystrophiesElizabeth M McNally; Fiscal Year: 2013..Core B will provide histopathological assessment of muscular dystrophy after genetic manipulation and treatments, and Core C will perform functional analysis in vivo and provide support to Core B. ..
- B-cell Biology of Mucosal Immune Protection from SIV ChallengeEric Hunter; Fiscal Year: 2013....
- Mitochondrial Target for Radiation MitigationJoel S Greenberger; Fiscal Year: 2013..abstract_text> ..
- Enteric nervous system deficits in Hirschsprung ganglionic bowelMELISSA MUSSER; Fiscal Year: 2013....
- Mechanisms of State Switching in Sleep and Sleep ApneaClifford B Saper; Fiscal Year: 2013..This work will help to design interventions for improving the health of patients with OSA. ..
- PAPOVA VIRUS TRANSFORMING MECHANISMSDAVID MORSE LIVINGSTON; Fiscal Year: 2013..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
- ACTIVATORS OF MUSCLE GENESHelen M Blau; Fiscal Year: 2013..The molecular insights gained will increase the clinical utility of muscle stem cells and increase our understanding of muscle biology and aging. ..
- Osteocyte Regulation of Bone/Muscle with Age Lynda F Bonewald; Fiscal Year: 2013..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
- Regulation of Stem Cell Self-renewal and DifferentiationMargaret T Fuller; Fiscal Year: 2013....
- Regulatory Mechanisms In Intestinal MotilityKenton 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 ..
- Mechanistic Pharmacology of Anti-Mitotics and Apoptosis RegulationTimothy J Mitchison; Fiscal Year: 2013..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
- Cardiac Fibrillation: Mechanisms and TherapyJames N Weiss; Fiscal Year: 2013..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
- Elafin Therapy for Lung DiseasesMarlene Rabinovitch; Fiscal Year: 2013..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
- Strategies for Improved Shock Wave LithotripsyJAMES 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 ..
- Biology and Novel Therapeutics of Cardiovascular PeptidesJohn C Burnett; Fiscal Year: 2013..Thus, this application brings together a highly collaborative team of physician-scientists with a highly translational proposal which should lead to innovative therapeutics for cardiorenal disease. ..
- Electrical control of gastric motilityKenton 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...