Roles of SLC26A6 in Renal NaCI Transport and Prevention of Oxalate Urolithiasis

描述（由申请人提供）：目前的提案是一个长期研究项目的延续，该项目旨在研究介导近端小管酸碱和NaCI运输的离子交换剂。作为该项目的一部分，申请人确定并表征了一种新型阴离子交换剂（SLC26A6），基于其介导cl -甲酸交换的能力，将其命名为CFEX。他们还发现，另一种相关的转运蛋白SLC26A7也在近端小管细胞的顶膜上表达。他们最近对CFEX小鼠的研究表明，CFEX由于其作为cl -草酸盐交换剂的活性，在近端小管NaCI吸收和肠道草酸盐分泌中起重要作用。他们证明后一过程对于限制草酸净肠吸收和预防高草酸尿和草酸钙尿石症至关重要。尽管申请者计划继续研究CFEX和SLC26A7在近端小管NaCI运输中的作用，但一项新的主要转化研究将集中在使用小鼠模型来阐明CFEX和相关转运体在草酸盐体内平衡的综合生理学以及高草酸尿和尿石症的发病机制中的作用。因此，本研究的具体目的是：1)评估CFEX在体内介导近端小管NaCI转运中的作用，并评估SLC26A7在介导非CFEX引起的近端小管Cl转运成分中的作用；2)评估CFEX在介导草酸近端小管转运中的作用，以及SLC26A7在介导非CFEX引起的草酸近端小管转运成分中的作用；3)评估CFEX介导肠道草酸转运的作用，并评估其他SLC26转运体在介导非CFEX的肠道草酸转运成分中的作用；4)评价CFEX突变在尿石症患者高草酸尿中的潜在作用；5)评价cfex相关蛋白在调节肠道草酸转运和草酸稳态中的作用。通过加强对影响尿草酸盐排泄的分子机制的理解，所提出的研究可能为结石风险增加的遗传原因提供新的见解，并可能确定新的治疗靶点来减少草酸盐排泄，从而降低结石风险。建议的研究也与临床疾病如高血压和充血性心力衰竭有关。

DESCRIPTION (provided by applicant): The present proposal is for continuation of a long-standing research program that had been directed at studying the ion exchangers mediating acid-base and NaCI transport in the proximal tubule. As part of this program, the applicants identified and characterized a novel anion exchanger (SLC26A6) that was named CFEX based on its ability to mediate Cl-formate exchange. They also found that a second related transporter, SLC26A7, is also expressed on the apical membrane of proximal tubule cells. Their recent studies using CFEX null mice have revealed that CFEX, by virtue of its activity as a Cl-oxalate exchanger, plays essential roles in proximal tubule NaCI absorption and intestinal oxalate secretion. They demonstrated that the latter process is critical to limiting net intestinal absorption of oxalate and preventing hyperoxaluria and calcium oxalate urolithiasis. Although the applicants plan to continue to examine the roles of CFEX and SLC26A7 in proximal tubule NaCI transport, a major new translational research effort will focus on the use of mouse models to elucidate the roles of CFEX and related transporters in the integrative physiology of oxalate homeostasis and the pathogenesis of hyperoxaluria and urolithiasis. Thus, the specific aims are to: 1) Evaluate the contribution of CFEX to mediating proximal tubule NaCI transport in vivo, and also assess the role of SLC26A7 in mediating components of proximal tubule Cl transport not attributable to CFEX; 2) Evaluate the role of CFEX in mediating proximal tubule oxalate transport, and also assess the role of SLC26A7 in mediating components of proximal tubule oxalate transport not attributable to CFEX; 3) Evaluate the role of CFEX in mediating intestinal oxalate transport, and also assess the role of other SLC26 transporters in mediating components of intestinal oxalate transport not attributable to CFEX; 4) Evaluate the potential role of CFEX mutations in causing hyperoxaluria in patients with urolithiasis; and 5) Evaluate the roles of CFEX-associated proteins in regulating intestinal oxalate transport and oxalate homeostasis. By enhancing understanding of the molecular mechanisms affecting urinary oxalate excretion, the proposed studies may provide new insight into genetic causes of increased stone risk, and may identify novel therapeutic targets to reduce oxalate excretion and thereby decrease stone risk. The proposed studies are also relevant to clinical disorders of NaCI homeostasis such as hypertension and congestive heart failure.