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

描述（由申请人提供）：本提案旨在继续一项长期研究计划，该计划旨在研究近端小管中介导酸碱和NaCl转运的离子交换剂。作为该计划的一部分，申请人鉴定并表征了一种新型阴离子交换剂（SLC 26 A6），基于其介导Cl-甲酸盐交换的能力将其命名为CFEX。他们还发现第二种相关的转运蛋白SLC 26 A7也在近端小管细胞的顶膜上表达。他们最近使用CFEX缺失小鼠的研究表明，CFEX凭借其作为Cl-草酸盐交换剂的活性，在近端小管NaCl吸收和肠草酸盐分泌中起着重要作用。他们证明，后一过程对限制草酸盐的净肠道吸收和预防高尿酸和草酸钙尿石症至关重要。尽管申请人计划继续检查CFEX和SLC 26 A7在近端小管NaCl转运中的作用，但主要的新的转化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盐稳态的综合生理学以及高尿酸和尿石症的发病机制中的作用。因此，具体的目的是：1）评估CFEX对体内介导近端小管NaCl转运的贡献，并且还评估SLC 26 A7在介导不归因于CFEX的近端小管Cl转运组分中的作用; 2）评估CFEX在介导近端小管草酸盐转运中的作用，还评估了SLC 26 A7在介导不归因于CFEX的近端小管草酸盐转运组分中的作用; 3）评估CFEX在介导肠草酸盐转运中的作用，并且还评估其他SLC 26转运蛋白在介导不归因于CFEX的肠草酸盐转运组分中的作用; 4）评估CFEX突变在尿石症患者中引起高尿酸的潜在作用;和5）评估CFEX相关蛋白在调节肠草酸盐转运和草酸盐稳态中的作用。通过加强对影响尿草酸排泄的分子机制的理解，拟议的研究可能会对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，以减少草酸排泄，从而降低结石风险。所提出的研究也与NaCl体内平衡的临床障碍相关，例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.