MOLECULAR AND CELLULAR BIOLOGY OF CYSTIC FIBROSIS

囊性纤维化的病因及相关研究进展 在过去的几年里，在检测和治疗方面取得了很大的进展。 使用与CF基因座紧密连锁的DNA序列可以实现产前 有家族病史和肺部疾病的诊断 移植正在延长一些患者的寿命。关于以下方面的线索 阴离子渗透性缺陷的性质导致了 上皮组织的病理变化提供了一些希望 可以开发出药物疗法。生病的医院 儿童基金会拥有一家非常大的诊所，长期致力于儿童基金会 许多正在进行的基础和临床研究项目。其中一些 项目构成了主要指导的CF研究开发计划 Cf基因的分子克隆及其在汗腺中的表达 上皮细胞培养系统。本申请意在 补充这一计划，进一步整合临床和基础科学 学习和利用该机构的几个优势，这些优势是 不包括在RDP中。中心主题是对 本病不同临床表型的基本缺陷 汗腺中DNA单倍型水平和离子传输机制， 肺和胰腺。因此，研究项目的目的是：1) 根尖基础的一种分子改变的鉴定 氯离子渗透性缺陷。2)相关关系的建立 囊性纤维化的临床和遗传变异之间的关系。3)使用 用于监测CF离子传输缺陷的光学成像技术。4) 肺泡上皮细胞离子转运特性的评价 在CF患者和正常人的肺组织中。5)考查 外向整流性阴离子通道在胰腺碳酸氢盐中的作用 分泌物6)该通道特性的比较 非上皮性细胞和上皮性细胞。两个核心设施 将是这些项目所需要的，也将极大地促进其他 Cf已经在进行中的项目。第一，收购和文化 来自胎肺泡和胰管的细胞将使 细胞和分子研究延伸到这些组织。第二, CF生物统计核心将提供对临床的便捷访问 我们庞大的CF患者群体的参数，从而使这些 与DNA单倍型和阴离子通道等特性相关 功能。

Progress towards understanding the etiology of Cystic Fibrosis as well as in detection and treatment has been substantial in the past few years. The use of DNA sequences closely linked to the CF locus enables prenatal diagnosis where there is a family history of the disease and lung transplantation is extending the life span of some patients. Clues about the nature of the anion permeability defect responsible for the pathological changes of epithelial tissues provide some hope that pharmacological therapies can be developed. The Hospital for Sick Children has a long term commitment to CF with a very large clinic and many ongoing research projects both basic and clinical. Some of these projects constitute a CF research Development Program directed primarily at the molecular cloning of the CF gene and its expression in sweat gland epithelial cell culture systems. The present application is intended to complement this program, to further integrate clinical and basic science studies and to exploit several strengths of this institution which are not included in the RDP. The central theme is the understanding of the basic defect in the different clinical phenotypes of the disease at the level of DNA haplotypes and ion transport mechanisms in the sweat gland, the lung and the pancreas. Hence the aims of the research project are; 1) The identification of a molecular alteration which underlies the apical chloride permeability defect. 2) The establishment of correlations between clinical and genetic variations in Cystic Fibrosis. 3) The use of optical imaging techniques to monitor CF ion transport defects. 4) The evaluation of the ion transport properties of alveolar epithelial cells of the lung in CF patients and normal subjects. 5) The examination of the role of the outwardly rectifying anion channel in pancreatic bicarbonate secretion 6) The comparison of the properties of this channel in nonepithelial cells with those in epithelial cells. Two core facilities will be required by these projects and will also greatly facilitate other CF projects which are already ongoing. First, the acquisition and culture of cells from the fetal lung alveolus and pancreatic duct will enable the cellular and molecular investigations to extend to these tissue. Second, the CF Biostatistics Core will provide ready access to clinical parameters of our large CF patient population and thus enable these to be correlated with properties such as DNA haplotypes and anion channel function.