Neurotrophins and Neuropeptides in Colon and Bladder Hypersensitivity

Summary

Principal Investigator: L-Y Qiao
Affiliation: Virginia Commonwealth University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Patients with inflammatory bowel disease often experience overactive bladder reflecting sensory hypersensitivity;however the mechanism underlying this clinical syndrome is not clear. Studies from our laboratory and others indicate that animal models of colitis demonstrate a similar cross-sensitization that leads to neurogenic bladder overactivity. Neuronal interaction at the level of primary afferents in dorsal root ganglia (DRG) and spinal cord likely plays a role in the colon-to-bladder hypersensitivity. The objective of this proposal is to investigate the role of neurotrophins as mediators of primary afferent cross-activation and hypersensitivity in colon-to-bladder sensitization following colitis induced by intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS) in rat. Our hypothesis is that colitis induces neuronal interaction between afferent neurons in DRG that is initiated, in part, by increases in nerve growth factor (NGF)/TrkA receptor and associated signaling pathways in colonic afferent neurons. This leads to increased expression of brain-derived neurotrophic factor (BDNF) in colonic afferents and increases in BDNF and TrkB in bladder afferent neurons. The increases in BDNF/TrkB and associated signaling pathways lead to subsequent induction of the excitatory neurotransmitter calcitonin gene-related peptide (CGRP) in bladder afferent neurons;BDNF and CGRP, in turn, lead to altered channel expression which mediates in part the hypersensitivity of bladder afferent neurons. The specific aims are: 1) characterization of NGF/TrkA and signaling pathway(s) in colonic afferent neurons that lead to the expression of BDNF in lumbosacral DRG following colitis;2) characterization of BDNF/TrkB and signaling pathways that lead to the expression of CGRP and ion channel(s) in bladder afferent neurons in DRG following colitis;and 3) characterization of the effects of BDNF and CGRP on the regulation of bladder hypersensitivity as measured by channel activity of bladder afferent neurons as well as bladder micturition parameters following colitis. The experiments will be done with a systematic approach involving measurements of neurotrophins, neuropeptides, and expression of their receptors and signaling pathways by direct measurements of signaling intermediates and use of antagonists, antisera, and selective inhibitors. The investigation of the mechanism underlying neuronal control of bladder and colon function in inflammation will advance understanding of this syndrome as well as suggest approaches for better control or treatment.
Funding Period: ----------------2008 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc In vivo regulation of brain-derived neurotrophic factor in dorsal root ganglia is mediated by nerve growth factor-triggered Akt activation during cystitis
    Li Ya Qiao
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
    PLoS ONE 8:e81547. 2013
  2. pmc Endogenous PI3K/Akt and NMDAR act independently in the regulation of CREB activity in lumbosacral spinal cord in cystitis
    Jarren C Kay
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
    Exp Neurol 250:366-75. 2013
  3. pmc Up-regulation of brain-derived neurotrophic factor is regulated by extracellular signal-regulated protein kinase 5 and by nerve growth factor retrograde signaling in colonic afferent neurons in colitis
    Sharon J Yu
    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23219, USA
    Exp Neurol 238:209-17. 2012
  4. pmc Activation of extracellular signal-regulated protein kinase 5 is essential for cystitis- and nerve growth factor-induced calcitonin gene-related peptide expression in sensory neurons
    Sharon J Yu
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
    Mol Pain 8:48. 2012
  5. pmc Regulation of IGF-1 but not TGF-β1 by NGF in the smooth muscle of the inflamed urinary bladder
    Qing L Zhang
    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
    Regul Pept 177:73-8. 2012
  6. pmc Prolonged sympathetic innervation of sensory neurons in rat thoracolumbar dorsal root ganglia during chronic colitis
    C M Xia
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Neurogastroenterol Motil 23:801-e339. 2011
  7. pmc Colitis elicits differential changes in the expression levels of receptor tyrosine kinase TrkA and TrkB in colonic afferent neurons: a possible involvement of axonal transport
    Li Ya Qiao
    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298 0551, USA
    Pain 151:117-27. 2010
  8. pmc Endogenous nerve growth factor regulates collagen expression and bladder hypertrophy through Akt and MAPK pathways during cystitis
    Chul Won Chung
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 0551, USA
    J Biol Chem 285:4206-12. 2010
  9. pmc Modulation of motor and sensory pathways of the peristaltic reflex by cannabinoids
    John R Grider
    Dept of Physiology and Biophysics, Box 980551, MCV Campus, Virginia Commonwealth Univ, Richmond, VA 23298 0551, USA
    Am J Physiol Gastrointest Liver Physiol 297:G539-49. 2009
  10. pmc Colitis induces calcitonin gene-related peptide expression and Akt activation in rat primary afferent pathways
    Li Ya Qiao
    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298 0551, USA
    Exp Neurol 219:93-103. 2009

Scientific Experts

  • L-Y Qiao
  • JOHN GRIDER
  • Sharon J Yu
  • Jarren C Kay
  • Chun Mei Xia
  • Qing L Zhang
  • Shanwei Shen
  • C M Xia
  • Chul Won Chung
  • Krystina B Hazelgrove
  • Miao Liu
  • Chulwon Chung
  • Melisa A Gulick
  • H I Akbarali
  • D G Colomb
  • Robert S Flynn
  • John F Kuemmerle

Detail Information

Publications11

  1. pmc In vivo regulation of brain-derived neurotrophic factor in dorsal root ganglia is mediated by nerve growth factor-triggered Akt activation during cystitis
    Li Ya Qiao
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States of America
    PLoS ONE 8:e81547. 2013
    ..These in vivo and in vitro experiments indicated that NGF played an important role in the activation of Akt and subsequent up-regulation of BDNF in the sensory neurons in visceral inflammation such as cystitis. ..
  2. pmc Endogenous PI3K/Akt and NMDAR act independently in the regulation of CREB activity in lumbosacral spinal cord in cystitis
    Jarren C Kay
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
    Exp Neurol 250:366-75. 2013
    ..These results suggest that PI3K/Akt and NMDAR independently regulate spinal plasticity in visceral pain model, and target of a single pathway is necessary but not sufficient in treatment of visceral hypersensitivity. ..
  3. pmc Up-regulation of brain-derived neurotrophic factor is regulated by extracellular signal-regulated protein kinase 5 and by nerve growth factor retrograde signaling in colonic afferent neurons in colitis
    Sharon J Yu
    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23219, USA
    Exp Neurol 238:209-17. 2012
    ....
  4. pmc Activation of extracellular signal-regulated protein kinase 5 is essential for cystitis- and nerve growth factor-induced calcitonin gene-related peptide expression in sensory neurons
    Sharon J Yu
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
    Mol Pain 8:48. 2012
    ..The molecular mechanism and signal transduction underlying cross talk between the inflamed urinary bladder and sensory sensitization has not been investigated...
  5. pmc Regulation of IGF-1 but not TGF-β1 by NGF in the smooth muscle of the inflamed urinary bladder
    Qing L Zhang
    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
    Regul Pept 177:73-8. 2012
    ..The up-regulation of NGF in the urothelium may have a role in affecting bladder smooth muscle cell physiology by regulating IGF-1 expression...
  6. pmc Prolonged sympathetic innervation of sensory neurons in rat thoracolumbar dorsal root ganglia during chronic colitis
    C M Xia
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Neurogastroenterol Motil 23:801-e339. 2011
    ..Peripheral irritation-induced sensory plasticity may involve catecholaminergic innervation of sensory neurons in the dorsal root ganglia (DRG)...
  7. pmc Colitis elicits differential changes in the expression levels of receptor tyrosine kinase TrkA and TrkB in colonic afferent neurons: a possible involvement of axonal transport
    Li Ya Qiao
    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298 0551, USA
    Pain 151:117-27. 2010
    ..These results suggested that colitis-induced primary afferent activation involved retrograde transport of TrkA but not TrkB from the distal colon to primary afferent neurons in DRG...
  8. pmc Endogenous nerve growth factor regulates collagen expression and bladder hypertrophy through Akt and MAPK pathways during cystitis
    Chul Won Chung
    Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 0551, USA
    J Biol Chem 285:4206-12. 2010
    ..These results indicate that endogenous NGF plays an important role in the activation of Akt and MAPK in the urinary bladder and in bladder hypertrophy during cystitis...
  9. pmc Modulation of motor and sensory pathways of the peristaltic reflex by cannabinoids
    John R Grider
    Dept of Physiology and Biophysics, Box 980551, MCV Campus, Virginia Commonwealth Univ, Richmond, VA 23298 0551, USA
    Am J Physiol Gastrointest Liver Physiol 297:G539-49. 2009
    ....
  10. pmc Colitis induces calcitonin gene-related peptide expression and Akt activation in rat primary afferent pathways
    Li Ya Qiao
    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298 0551, USA
    Exp Neurol 219:93-103. 2009
    ..These results suggest that CGRP is synthesized in the DRG and may transport to the spinal cord where it initiates signal transduction during colitis...
  11. pmc Endogenous IGF-I and alpha v beta3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis
    Krystina B Hazelgrove
    Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth Univ, PO Box 980711, Richmond, VA 23298 0711, USA
    Am J Physiol Gastrointest Liver Physiol 296:G1230-7. 2009
    ..This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease...