BYPASSING THE SECRETORY DEFECT IN CYSTIC FIBROSIS

描述(改编自申请者摘要)：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，尤其是与胃肠道有关的 胎粪性肠梗阻等表现。囊性纤维化是最常见的， 高加索血统的人患有严重的常染色体隐性遗传病。 该病是一种上皮运输障碍，并导致 严重的发病率和预期寿命缩短。囊肿性疾病患者 纤维化本质上缺乏cAMP调节的氯化物分泌 各种组织，包括呼吸道、胰腺和胆道系统，以及 肠子。在呼吸道中，氯化物有另一种途径。 细胞内钙和a增加所介导的转运 钙激活氯离子通道(CACC)。然而，无论是阵营还是 肠道中的钙调节通路是有缺陷的。的基础 肠道中没有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 这种疾病的表现。在这方面，调查人员已经表明， 正常的肠上皮细胞表达激动剂敏感的、固有的 限制基因表达的负性调控信号机制 依赖钙离子的氯化物分泌。调查人员假设 这种机制也可能存在于囊性纤维化的肠道中，并且 想办法绕过这些抑制信号可能是有治疗作用的 利益。研究人员将使用互补细胞的组合 培养、电生理、动物和分子检测方法 三个具体目标。首先，调查员将确定是否有 是负面信号表达的根本区别 呼吸道和肠道上皮细胞之间的通路。第二， 调查人员将确定这些负面信号是否确实存在 囊性纤维化肠管不能分泌氯化物的原因 对钙依赖激动剂的反应。第三，调查人员将 确定分子机制(S)，其中一个关键的负面信号， 肌醇3，4，5，6四氢磷酸，发挥其抑制作用，以及 探索绕过这种抑制的方法。总而言之，这些研究应该 提高对囊性纤维化的认识和治疗 一般情况下，特别是关于新生儿胃肠道 可能会产生严重的长期健康后果的表现。

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.