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

SLC26A6 在肾 NaCl 转运和预防草酸尿石症中的作用

• 批准号: 7850073
• 负责人: PETER S. ARONSON
• 金额: $ 3.58万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7850073
• 关键词: Acids; Acute; Address; Affect; Anions; Biological Assay; Calcium Oxalate; Calculi; Cells; Clinical; Congestive Heart Failure; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Disease; Distal; Diuretics; Evaluation; Excretory function; Formates; Genetic; Heterozygote; Homeostasis; Human; Hyperoxaluria; Hypertension; Intestinal Absorption; Intestines; Ions; Kidney; Knockout Mice; Large Intestine; Measures; Mediating; Micropuncture; Molecular; Mus; Mutation; Names; Nephrons; Oxalates; Pathogenesis; Patients; Phenotype; Physiological; Physiology; Plasma; Play; Prevention; Process; Protein Isoforms; Proteins; Research; Research Personnel; Risk; Role; Testing; Time; Translational Research; Variant; Vesicle; Work; absorption; apical membrane; base; in vivo; insight; mouse model; new therapeutic target; novel; prevent; programs; research study; urinary; urolithiasis

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.

描述（由申请人提供）：本提案是为了继续一项长期研究计划，该计划旨在研究介导近曲小管中酸碱和氯化钠运输的离子交换剂。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（SLC26A6），基于其介导氯-甲酸盐交换的能力，将其命名为 CFEX。他们还发现，第二种相关转运蛋白 SLC26A7 也在近曲小管细胞的顶膜上表达。他们最近使用 CFEX 缺失小鼠进行的研究表明，CFEX 凭借其作为 Cl-草酸盐交换剂的活性，在近端小管 NaCl 吸收和肠道草酸盐分泌中发挥重要作用。他们证明，后一个过程对于限制草酸盐的肠道净吸收和预防高草酸尿症和草酸钙尿石症至关重要。尽管申请人计划继续研究 CFEX 和 SLC26A7 在近曲小管 NaCl 转运中的作用，但一项重大的新转化研究工作将集中于使用小鼠模型来阐明 CFEX 和相关转运蛋白在草酸稳态综合生理学中的作用以及高草酸尿症和尿石症的发病机制。因此，具体目标是：1)评估CFEX在体内介导近端小管NaCI转运的贡献，并评估SLC26A7在介导不可归因于CFEX的近端小管Cl转运成分中的作用； 2)评估CFEX在介导近曲小管草酸转运中的作用，并评估SLC26A7在介导不可归因于CFEX的近曲小管草酸盐转运成分中的作用； 3）评估CFEX在介导肠道草酸盐转运中的作用，并评估其他SLC26转运蛋白在介导非CFEX的肠道草酸盐转运成分中的作用； 4) 评估CFEX突变在引起尿石症患者高草酸尿症中的潜在作用； 5) 评估 CFEX 相关蛋白在调节肠道草酸盐转运和草酸盐稳态中的作用。通过增强对影响尿草酸盐排泄的分子机制的理解，拟议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以减少草酸盐排泄，从而降低结石风险。拟议的研究还与氯化钠稳态的临床疾病相关，例如高血压和充血性心力衰竭。