钠离子偶联的HCO3-转运体NBCn2（简称n2）是一个重要的pH调控蛋白，与多种人类疾病有着密切关联。在前期研究中，我们发现编码n2的基因SLC4A10具有三个启动子，其中一个控制一类我们新发现的n2剪接异构体在肾脏中的特异表达。这也是首次阐明n2在肾脏中有表达！肾脏是极为重要的过滤与重吸收器官，肾脏碳酸氢根重吸收对于维持机体的酸碱稳态有很关键的作用。在此，我将对n2在肾脏酸碱平衡调控分子机制中的作用进行研究。研究内容主要包括：①通过报告基因研究n2的不同启动子在肾脏模式细胞HEK293等细胞系中的表达特异性及其对酸碱刺激的应答机制；②阐明n2在肾小管上皮细胞中的表达定位；③通过代谢性酸中毒等模型研究n2在肾脏中的作用；④通过电生理学技术研究n2异构体的离子转运活性。这些研究将对从基因、分子、系统水平了解n2在机体酸碱平衡调控机制中的作用及代谢性酸中毒的病理机制具有重要科学意义。

It is of fundamental significance to maintain acid-base homeostasis in the body. The electroneutral sodium coupled HCO3- transporter NBCn2, encoded by SLC4A10 which belongs to the solute carrier family 4 (SLC4), plays critical roles in intracellular pH regulation as well as transepithelial HCO3- movement. In human, dysfunction of SLC4A10 is associated with multiple pathological conditions. By 5'-RACE and cDNA cloning, we have identified a series of novel NBCn2 variants. Our data indicate that SLC4A10 contains three distinct promoters in charge of expression of NBCn2 variants with different amino termini. One of these promoters is responsible for the specific expression of a type of NBCn2 in the kidney-the first demonstration that NBCn2 is expressed in the kidney. It is well known that HCO3- reabsorption by renal tubules plays an essentially important role maintaining global acid-base homeostasis in the body. In the present study, we will investigate the role of NBCn2 in acid-base transport in the kidney. First, using luciferase reporter assay, we will elucidate the cell-type specificity of different promoters of Slc4a10 in different model cell lines, as well as the response of these promoters to acid stimuli in cell culturte. Second, to understand the physiological role of NBCn2 in the kidney, we will examine, by immunocytochemistry, the cellular localization of NBCn2 proteins in renal tubules. Thirdly, we will examine the effect of acid-base stress, including metabolic acidosis, chronic hypoxia, on the expression of NBCn2 in rat kidney. Finally, we will investigate the effect of structural variations of NBCn2 variants on the HCO3- transport activities of the transporter. Our study will provide, from the gene, molecular, as well as system levels, critical insights into our understanding of the physiological as well as pathological roles of NBCn2 in the kidney.