BYPASSING THE SECRETORY DEFECT IN CYSTIC FIBROSIS

描述（改编自申请人摘要）：长期目标是 开发可能有助于理解和治疗的信息 囊性纤维化，特别是关于其胃肠道 胎粪性肠梗阻等临床表现。 囊性纤维化是最常见的， 高加索人中的严重常染色体隐性遗传疾病。 该疾病是上皮转运障碍，并导致 发病率高，预期寿命缩短。 例囊性 纤维化基本上不存在cAMP调节氯分泌， 各种组织，包括气道、胰腺和胆道系统，以及 肠子 在呼吸道中，氯化物有一个替代途径 通过增加细胞内钙离子介导的转运， 钙激活氯离子通道（CaCC）。 然而，cAMP和 钙介导的途径在肠中是有缺陷的。 的基础 肠中缺乏钙介导的分泌尚不清楚，但可能 在胃肠道疾病的发病机制中起重要作用 疾病的表现。 对此，调查人员表示， 正常的肠上皮细胞表达激动剂敏感的，内在的 负调控信号机制，限制表达 钙依赖性氯化物分泌。 研究人员假设， 这种机制也可能存在于囊性纤维化肠中， 设计出避开这些抑制信号的方法可能是治疗性的， 效益 研究人员将使用互补细胞的组合 培养、电生理学、动物和分子方法来检查 三个具体目标。 首先，调查人员将确定是否有 在表达消极信号方面有着根本的不同， 气道和肠上皮细胞之间的通路。 二是 调查人员将确定这些负面信号是否真的 说明囊性纤维化肠不能分泌氯化物， 对钙依赖性激动剂的反应。 第三，调查人员将 确定一个关键的负信号的分子机制， 肌醇3，4，5，6四磷酸，发挥其抑制作用，和 探索规避这种抑制的方法。 总的来说，这些研究应 提高我们对囊性纤维化的理解和治疗， 一般，特别是对于新生儿胃肠道 可能会对健康造成严重的长期后果。

DESCRIPTION (Adapted from applicant's abstract): The long-term goal is to develop information that may be useful in the understanding and treatment of cystic fibrosis, particularly with regard to its gastrointestinal manifestations such as meconium ileus. Cystic fibrosis is the most common, severe, autosomal recessive disorder among individuals of Caucasian origin. The disease is a disorder of epithelial transport, and results in significant morbidity and reduced life expectancy. Patients with cystic fibrosis have essentially absent cAMP-regulated chloride secretion in various tissues, including the airways, pancreatic and biliary systems, and the intestine. In the airways, there is an alternate pathway for chloride transport mediated by increases in intracellular calcium and a calcium-activated chloride channel (CaCC). However, both the cAMP and calcium-mediated pathways are defective in the intestines. The basis for the absent calcium-mediated secretion in the intestine is unknown, but may contribute significantly to the pathogenesis of gastrointestinal manifestations of the disease. In this regard, the investigators have shown that normal intestinal epithelial cells express agonist-sensitive, intrinsic negative regulatory signalling mechanisms that limit the expression of calcium-dependent chloride secretion. The investigators hypothesize that such mechanisms may also exist in the cystic fibrosis intestine, and that devising ways to circumvent these inhibitory signals may be of therapeutic benefit. The investigator will use a combination of complementary cell culture, electrophysiological, animal and molecular approaches to examine three specific aims. First, the investigator will determine whether there are fundamental differences in the expression of negative signalling pathways between airway and intestinal epithelial cells. Second, the investigators will determine whether such negative signals do in fact account for the failure of cystic fibrosis intestine to secrete chloride in response to calcium-dependent agonists. Third, the investigators will determine the molecular mechanism(s) whereby one key negative signal, inositol 3,4,5,6 tetrakisphosphate, exerts its inhibitory effects, and explore ways to circumvent this inhibition. In total, the studies should improve our understanding and the therapy of cystic fibrosis, both in general, and specifically with respect to the neonatal gastrointestinal manifestations that may have severe long-term health consequences.