NBC1 and Proximal RTA: Pathogenesis and Treatment

NBC1 和近端 RTA：发病机制和治疗

基本信息

批准号：
8063639
负责人：
IRA KURTZ
金额：
$ 30.32万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-12-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8063639
关键词：
Address Affect Aminoglycosides Anabolism Animal Model Bicarbonates Biochemical Pathway Biological Brain Carrier Proteins Cell membrane Cells Cellular biology Cloning Data Defect Deletion Mutation Disease Distal renal tubular acidosis Type 1 Drug or chemical Tissue Distribution Erythrocyte Anion Exchange Protein 1 Eye Family Future Gene Abnormality Genetic Goals Health Hereditary Disease Hereditary Spherocytosis Human Impairment Inherited Kidney Knowledge Laboratories MDCK cell Mammalian Cell Mediating Membrane Transport Proteins Metabolic acidosis Missense Mutation Modality Molecular Mutation Nonsense Codon Nonsense Mutation Organelles Pancreas Pathogenesis Patients Peptides Physiological Play Property Proteins Proton Pump Proximal Renal Tubular Acidosis Reading Regulation Renal tubular acidosis Research Personnel Role Severities Sodium-Bicarbonate Symporters System Testing Therapeutic Therapy Clinical Trials Tissues absorption aminoglycoside-induced ototoxicity antibiotic G 418 base body system design improved man member mutant nephrotoxicity new therapeutic target novel strategies novel therapeutics programs research study small molecule therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): Renal tubular acidosis is an important cause of metabolic acidosis in patients. In patients with proximal renal tubular acidosis (RTA), the severity of the metabolic acidosis tends to be greater than patients with distal RTA. Metabolic acidosis can affect important biochemical pathways and perturb the function of various organ systems. Patients with renal tubular acidosis often have extrarenal manifestations that cannot be treated effectively with base therapy. Unfortunately, we currently lack specific treatments that target the underlying transport abnormalities in the proximal tubule and in extrarenal tissues. Recent advances in our understanding of the underlying transport defects in patients with genetic forms of RTA offer a unique opportunity to devise specific therapeutic approaches that target specific transporter mutations. The focus of this proposal is on the molecular pathogenesis and treatment of autosomal recessive proximal RTA. Hereditary proximal renal tubular acidosis results from mutations in the SLC4A4 electrogenic sodium bicarbonate cotransporter NBC1. NBC1 is responsible for mediating basolateral bicarbonate absorption in the proximal tubule and bicarbonate transport in extrarenal tissues including the pancreas, eye, and brain. Mutations in the NBC1 transporter presents a therapeutic challenge given the known missense, nonsense, and deletion mutations that decrease cotransporter function in this disorder. In preliminary experiments, we have begun to fill the current gap in our understanding of the biosynthesis, structural properties, organelle trafficking, and functional abnormalities of mutant cotransporters, with the goal of devising targeted therapeutic strategies for specific classes of NBC1 mutations. Our experiments have utilized mammalian HEK-293 and mPCT expression systems to address the aims of this proposal. The novelty of this proposal is that new therapeutic modalities have been found in preliminary studies that can potentially target specific NBC1 mutations causing proximal RTA. The data obtained from the results of this proposal could provide an important basis for future therapy of this disease in humans. The experiments in this proposal will confirm our preliminary findings, define the physiologic and molecular mechanisms underlying novel approaches for treating specific NBC1 mutations, and potentially play a role in therapeutic trials in animal models and ultimately patients with proximal renal tubular acidosis.

描述（申请人提供）：肾小管性酸中毒是患者代谢性酸中毒的重要原因。近端肾小管酸中毒 (RTA) 患者的代谢性酸中毒严重程度往往高于远端 RTA 患者。代谢性酸中毒会影响重要的生化途径并扰乱各种器官系统的功能。肾小管性酸中毒患者常有肾外表现，基础治疗无法有效治疗。不幸的是，我们目前缺乏针对近曲小管和肾外组织中潜在运输异常的具体治疗方法。我们对 RTA 基因型患者潜在转运缺陷的了解的最新进展，为设计针对特定转运蛋白突变的特定治疗方法提供了独特的机会。该提案的重点是常染色体隐性近端 RTA 的分子发病机制和治疗。遗传性近端肾小管酸中毒是由 SLC4A4 电动碳酸氢钠协同转运蛋白 NBC1 突变引起的。 NBC1 负责介导近端小管中基底外侧碳酸氢盐的吸收以及肾外组织（包括胰腺、眼睛和大脑）中碳酸氢盐的转运。鉴于已知的错义、无义和缺失突变会降低这种疾病中的协同转运蛋白功能，NBC1 转运蛋白的突变提出了治疗挑战。在初步实验中，我们已经开始填补目前对突变协同转运蛋白的生物合成、结构特性、细胞器运输和功能异常的理解空白，目标是针对特定类别的 NBC1 突变设计有针对性的治疗策略。我们的实验利用哺乳动物 HEK-293 和 mPCT 表达系统来解决该提案的目标。该提案的新颖之处在于，初步研究中发现了新的治疗方式，可以潜在地针对引起近端 RTA 的特定 NBC1 突变。从该提案的结果中获得的数据可以为未来治疗人类这种疾病提供重要的基础。本提案中的实验将证实我们的初步发现，定义治疗特定 NBC1 突变的新方法的生理和分子机制，并可能在动物模型和最终近端肾小管酸中毒患者的治疗试验中发挥作用。