CONTROL OF COLONIC MOTILITY IN HEALTH AND DISEASE

特发性人类溃疡性结肠炎患者结肠动力异常 结肠炎以及结肠炎症的动物模型的特征在于 通过抑制节律性阶段性收缩，降低n音调， 巨移行性收缩（GMC）的频率增加。 这些 运动异常在产生 腹泻、排便急迫和腹部绞痛。 蜂窝 的张力，阶段性收缩和GMC的产生机制， 结肠未知。 本提案的第一个目的是调查 特定信号转导通路在音调产生中的作用， 刺激结肠的阶段性收缩。 第二个目标是 确定这些信号转导途径是如何被调节的， 炎症反应，以抑制张力和阶段性收缩。 关键 细胞内信使包括胞质游离Ca 2+， 细胞内储存，IP3，DAG和PKC，将被测量，以支持 生理学和药理学观察。 膜片钳研究将在 在新鲜分离的细胞和取自 正常和发炎的犬结肠。 广泛的体内和体外数据， 可以帮助我们解释我们的数据， 将其与临床疾病联系起来。 粘多糖暴露于乙醇和乙酸 酸将被用于诱发炎症。 运动异常， 该模型类似于在人溃疡性结肠炎中报道的那些。 一个 了解不同的信号转导途径， 产生张力和刺激阶段性收缩可能提供机会 来分别调节每种收缩。 在 炎症性肠病和其他形式的肠道炎症， 期望选择性地刺激阶段性收缩和紧张， 减少腹泻、排便急迫和腹部不适。

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.