Stress evokes and exacerbates the symptoms of irritable bowel syndrome. Corticotropin-releasing factor (CRF) plays a major role in the coordination of the body's overall responses to stress, including the gut. The role of central CRF acting on brain CRF1 receptors in stress-related stimulation of colonic motility is well characterized, but the peripheral actions of CRF and its related peptide urocortin 1 (Ucn1) in regulating colonic motility, independent of their """"""""central"""""""" actions, remains ambiguous. This proposal is designed to test a hypothesis that peripheral CRF- or Ucn1-mediated signaling in the enteric nervous system of the gut is pivotal in regulating colonic motor and secretory responses to stress. By using a novel technique of colon-specific RNA interference (RNAi), we will knockdown CRF peptides or CRF receptors in the colon and test whether endogenous CRF peptides in the gut are required for stress-induced stimulation of colonic motility and secretion. Using c-fos expression as a marker for neural activation and double labeling immunohistochemistry with CRF or Ucn1 antibody, we will be able to determine if CRF or Ucn1 neurons in the enteric nervous system are activated during stress. Enzyme-linked fluorescence immunoassays will be used to determine if CRF or Ucn1 is released locally in the colon during stress. Intracellular """"""""sharp"""""""" microelectrode recording on single colonic neurons will be used to investigate CRF/Ucn1 signaling mechanisms in the enteric nervous system during stress. These results have potential to fill in a gap of knowledge regarding how stress affects colonic function. It is expected to establish the critical role of endogenous CRF peptides in the gut in colonic response to stress. Knowledge of CRF peptides signaling pathways in the enteric nervous system will shed light on the development of novel therapeutic strategies for stress-related functional bowel disorders (e.g., irritable bowel syndrome) by selectively targeting the enteric CRF peptides signaling systems.
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