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: 7921096
• 负责人: PETER S. ARONSON
• 金额: $ 13.54万
• 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: 2009-09-28 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921096
• 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）：目前的提案是为了延续一项长期研究计划，该计划旨在研究介导酸碱和NACI在近端小管中的离子交换器。作为该计划的一部分，申请人确定并表征了一种新型的阴离子交换器（SLC26A6），该杂货基于介导Cl构型交换的能力而命名为CFEX。他们还发现，第二个相关的转运蛋白SLC26A7在近端小管细胞的顶膜上也表达。他们使用CFEX无效小鼠的最新研究表明，CFEX凭借其作为Cl-Oxalate交换器的活性在近端小管NACI吸收和肠道草酸盐分泌中起着重要作用。他们证明，后一个过程对于限制草酸盐的净肠吸收至关重要，并预防高黄油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NACI近端NACI运输中的作用，但主要的新转化研究工作将集中于使用鼠标模型来阐明CFEX和相关转运蛋白在Oxalate稳态的综合生理学中的作用，以及Hyperoxaluria and Hyperoxaluria and Hyperoxaluria and Hyperoxaluria和Hyperoxaluria和Hypercaluriasis。因此，具体的目的是：1）评估CFEX在体内介导近端NACI转运的贡献，并评估SLC26A7在介导近端小管转运的组件中的作用； 2）评估CFEX在介导近端小管中的作用，并评估SLC26A7在介导近端小管的近端小管转运的成分中的作用，而不是CFEX归因于CFEX； 3）评估CFEX在介导草酸盐转运中的作用，并评估其他SLC26转运蛋白在介导的肠道肠道成分中的作用，而不是CFEX归因于CFEX； 4）评估CFEX突变在引起尿石症患者中的高黄油中的潜在作用； 5）评估CFEX相关蛋白在调节草酸肠运输和草酸盐稳态中的作用。通过增强对影响草酸尿液排泄的分子机制的理解，提出的研究可能会提供对增加石材风险增加的遗传原因的新见解，并可以鉴定出新的治疗靶标，从而减少草酸盐排泄，从而降低石材风险。拟议的研究还与NACI稳态的临床疾病有关，例如高血压和充血性心力衰竭。