A mathematical model of ENaC and Slc26a6 regulation by CFTR in salivary gland ducts.
A mathematical model of ENaC and Slc26a6 regulation by CFTR in salivary gland ducts.
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唾液腺导管中 CFTR 调节 ENaC 和 Slc26a6 的数学模型。
DOI：
10.1152/ajpgi.00168.2023
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Sneyd,James
中科院分区：
文献类型：
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作者：
Su,Shan;Wahl,Amanda;Rugis,John;Suresh,Vinod;Yule,DavidI;Sneyd,James
囊性纤维化（CF）是一种由囊性纤维化跨膜电导调节基因（CFTR）突变引起的遗传性疾病。 Cftr 是在小鼠唾液腺横纹管细胞顶膜中表达的关键离子通道。尽管 Cftr 主要是 Cl− 通道，但其敲除会导致唾液中 Cl− 和 Na+ 浓度升高以及 pH 值降低。小鼠实验表明，Cftr 的激活可上调上皮 Na+通道 (ENaC) 蛋白表达水平和 Slc26a6（溶质载体家族的 1Cl−:2 交换剂）活性。实验上很难预测 CFTR 的共调节作用对 CF 唾液中 Na+、Cl− 以及浓度和 pH 值异常的影响有多大。为了解决这个问题，我们构建了野生型小鼠唾液腺模型，并通过改变 CFTR、ENaC 和 Slc26a6 的表达水平来模拟 CFTR 敲除。通过重现野生型和 CFTR 敲除动物的体内和离体最终唾液测量结果，我们获得了计算证据，表明唾液腺中 CFTR 敲除动物中 ENaC 和 Slc26a6 的活性被下调。新内容和值得注意的是本文描述了模拟唾液和唾液腺导管上皮之间离子交换的唾液腺数学模型。新颖之处在于在 CFTR 敲除腺体中实施 CFTR 调节 ENaC 和 Slc26a6。通过重现野生型和 CFTR 敲除腺体中的实验唾液测量结果，该模型表明 CFTR 调节唾液腺中的 ENaC 和 Slc26a6 阴离子交换剂。该方法可用于了解各种囊性纤维化表型。
Cystic fibrosis (CF) is a genetic disease caused by the mutations of cystic fibrosis transmembrane conductance regulator (CFTR), the cystic fibrosis transmembrane conductance regulator gene. Cftr is a critical ion channel expressed in the apical membrane of mouse salivary gland striated duct cells. Although Cftr is primarily a Cl−channel, its knockout leads to higher salivary Cl−and Na+concentrations and lower pH. Mouse experiments show that the activation of Cftr upregulates epithelial Na+channel (ENaC) protein expression level and Slc26a6 (a 1Cl−:2exchanger of the solute carrier family) activity. Experimentally, it is difficult to predict how much the coregulation effects of CFTR contribute to the abnormal Na+, Cl−, andconcentrations and pH in CF saliva. To address this question, we construct a wild-type mouse salivary gland model and simulate CFTR knockout by altering the expression levels of CFTR, ENaC, and Slc26a6. By reproducing the in vivo and ex vivo final saliva measurements from wild-type and CFTR knockout animals, we obtain computational evidence that ENaC and Slc26a6 activities are downregulated in CFTR knockout in salivary glands.NEW & NOTEWORTHYThis paper describes a salivary gland mathematical model simulating the ion exchange between saliva and the salivary gland duct epithelium. The novelty lies in the implementation of CFTR regulating ENaC and Slc26a6 in a CFTR knockout gland. By reproducing the experimental saliva measurements in wild-type and CFTR knockout glands, the model shows that CFTR regulates ENaC and Slc26a6 anion exchanger in salivary glands. The method could be used to understand the various cystic fibrosis phenotypes.