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

描述(由申请人提供)：本提案是为了继续一项长期的研究计划，该计划旨在研究离子交换器在近端小管中调节酸碱和NaCI的运输。作为该计划的一部分，申请者确定并表征了一种新型阴离子交换剂(SLC26A6)，该阴离子交换剂因其介导氯甲酸盐交换的能力而被命名为CFEX。他们还发现，第二个相关的转运蛋白SLC26A7也表达在近端小管细胞的顶膜上。他们最近在CFEX缺失小鼠身上的研究表明，CFEX作为一种氯-草酸交换活性，在近端小管NaCI吸收和肠道草酸分泌中发挥着重要作用。他们证明，后一个过程对于限制草酸的肠道净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转运中的作用，但一项重大的新的翻译研究工作将集中在使用小鼠模型来阐明CFEX和相关转运蛋白在草酸稳态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所致的近端小管氯转运中的作用；2)评估CFEX在介导近端小管草酸转运中的作用，并评估SLC26A7在非CFEX所致的近端小管草酸转运中的中介作用；3)评估CFEX在调节肠道草酸转运中的作用，以及评估其他SLC26转运体在调节非CFEX所致的肠道草酸转运中的作用；4)评估CFEX突变在导致尿石症患者高氧尿症中的潜在作用；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排泄的分子机制的了解，拟议的研究可能为增加结石风险的遗传原因提供新的见解，并可能找到减少草酸排泄从而降低结石风险的新的治疗靶点。拟议的研究也与NACI稳态的临床障碍有关，如高血压和充血性心力衰竭。

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.