CONTROL OF COLONIC MOTILITY IN HEALTH AND DISEASE

描述：特发性溃疡患者结肠运动异常

DESCRIPTION: Abnormal colonic motility in idiopathic human ulcerative colitis as well as in animal models of colonic inflammation is characterized by the suppression of rhythmic phasic contractions, decrease n tone and increase in the frequency of giant migrating contraction (GMCs). These motility abnormalities play a key role in producing the symptoms of diarrhea, urgency of defecation and abdominal cramping. The cellular mechanisms for the generation of tone, phasic contractions and GMCs in the colon are not known. The first aim of this proposal is to investigate the roles of specific signal transduction pathways in the generation of tone and stimulation of phasic contractions in the colon. The second aim is to determine how these signal transduction pathways are modulated by the inflammatory response to suppress the tone and phasic contractions. Key intracellular messengers including cytosolic free Ca2+, Ca2+ efflux from intracellular stores, IP3, DAG and PKC, will be measured to support the physiological and pharmacological observations. Patch clamp studies will be done on freshly dissociated cells and circular muscle strips taken from normal and inflamed canine colon. Extensive in vivo and in vitro data are available from this species to help in the interpretation of our data and relating it to clinical diseases. Mucosal exposure to ethanol and acetic acid will be used to induce inflammation. The motility abnormalities in this model are similar to those reported in human ulcerative colitis. An understanding of the differences n signal transduction pathways that generate tone and stimulate phasic contractions may present the opportunity to regulate each type of contraction separately from the other. In inflammatory bowel disease and other forms of gut inflammation it would be desirable to selectively stimulation phasic contractions and tone to minimize diarrhea, urgency of defecation and abdominal discomfort.