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. ? ? ?
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