CL-/HCO3- EXCHANGE IN CYSTIC FIBROSIS SWEAT GLANDS

囊性纤维化汗腺中的 CL-/HCO3- 交换

基本信息

批准号：
6381310
负责人：
PAUL M QUINTON
金额：
$ 25.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-28 至 2004-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6381310
关键词：
apical membrane basolateral membrane bicarbonates biopsy chloride channels chloride ion clinical research cystic fibrosis epithelium genotype human subject ion transport membrane permeability protein localization sweat glands voltage /patch clamp

项目摘要

The most common and characteristic physiological defect of Cystic Fibrosis (CF) is dysfunction of the CFTR C1-channel which blocks C1- transport. On the other hand, it is not widely appreciated that HCO3 ion-transport is also defective in most, if not all, organs affected in CF. In view of its critical role in setting pH and its known ability to exchange for C1-ions, abnormalities in HCO3 ion-management may be closely integrated with CF pathogenesis. The link between these two defects is not known, but the human sweat duct offers a unique opportunity to observe normal and defective C1-and HCO3 ion-transport in a native human tissue where the effects of CF markedly disturb electrolyte transport. Our data and other evidence indicates that HCO3 ion-is most probably transported via a C1-/HCO3 ion-anion exchange (AE) as it is in most other tissues. We propose to define AE function in sweat ducts from normal subjects and CF patients. We will characterize AE activity and HCO3 ion-transport in the plasma membranes of duct cells. Then, since electrochemical results show that not all C1- absorption in the duct can occur electroconductively through CFTR, we will determine whether AE activity accounts for the difference. Because phosphorylation state, ATP, and pH strongly influence CFTR activity and because C1-conductance and HCO3 ion-transport function together, we will determine whether any of these parameters regulate or influence HCO3 ion-transport also. Lastly, the severity of the HCO3 ion-transport defect appears to vary with distinct genotypes so we will use ducts from patients with known mutations in CFTR to determine if these mutations exert distinct effects on HCO3 ion-transport in the sweat duct. At present it is difficult to rationalize how a simple singular defect in C1-conductance can cause the myriad of abnormalities found in CF: namely, salty sweat, autolysis of the pancreas, atresia of the vas deferens, meconium ileus, depressed female fertility, and lung disease as well as a host of other abnormalities. Defining HCO3 ion-transport and its relevance to CFTR function should lend much to explaining, and hopefully, ameliorating these problems.

囊性最常见和特征的生理缺陷纤维化（CF）是CFTR C1通道的功能障碍，该通道阻塞C1- 运输。另一方面，HCO3并非广泛赞赏离子传输在大多数（如果不是全部）的器官中也有缺陷参见鉴于其在设定pH和已知能力方面的关键作用为了交换C1-ives，HCO3离子管理异常可能是与CF发病机理紧密整合。这两个之间的链接缺陷尚不清楚，但是人类的汗水提供了独特的观察正常和有缺陷的C1和HCO3离子传输的机会在本地人类组织中，CF的影响明显干扰电解质传输。我们的数据和其他证据表明HCO3 离子 - 很可能是通过C1-/HCO3离子 - 阳离子交换（AE）运输的就像大多数其他组织一样。我们建议在来自正常受试者和CF患者的汗管。我们将表征 AE活性和HCO3离子传输在质膜中细胞。然后，由于电化学结果表明，并非所有C1- 管道中的吸收可以通过CFTR进行电导性，我们将确定AE活动是否解释了差异。因为磷酸化状态，ATP和pH强烈影响CFTR活性和因为C1-导导和HCO3离子传输功能一起，我们将确定这些参数中的任何一个是否调节或影响HCO3 离子传输也是如此。最后，HCO3离子传输的严重程度缺陷似乎随着不同的基因型而变化，因此我们将使用来自 CFTR中有已知突变的患者，以确定这些突变是否对汗管中的HCO3离子传输产生明显的影响。目前很难合理化简单的单数缺陷在C1传统中，CF中发现了无数异常。即，咸汗，胰腺自溶，VAS的闭锁递延，幼虫，女性抑郁和肺部疾病以及许多其他异常。定义HCO3离子传输它与CFTR函数的相关性应大大解释，并且希望可以改善这些问题。