NBC1 and Proximal RTA: Pathogenesis and Treatment

描述（由申请方提供）：肾小管性酸中毒是患者代谢性酸中毒的重要原因。在近端肾小管酸中毒（RTA）患者中，代谢性酸中毒的严重程度往往大于远端RTA患者。代谢性酸中毒可以影响重要的生化途径，扰乱各种器官系统的功能。肾小管性酸中毒患者常伴有基础治疗不能有效治疗的肾外表现。不幸的是，我们目前缺乏针对近端小管和肾外组织中潜在转运异常的特异性治疗。我们对遗传性RTA患者潜在转运缺陷的理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。该建议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由SLC 4A 4产电碳酸氢钠协同转运蛋白NBC 1突变引起。NBC 1负责介导近端小管中的基底外侧碳酸氢盐吸收和肾外组织（包括胰腺、眼睛和大脑）中的碳酸氢盐转运。NBC 1转运蛋白的突变提出了一个治疗挑战，因为已知的错义、无义和缺失突变会降低这种疾病中的协同转运蛋白功能。在初步的实验中，我们已经开始填补目前的空白，在我们的理解的生物合成，结构特性，细胞器贩运，和功能异常的突变cotorporters，与设计针对特定类别的NBC 1突变的治疗策略的目标。我们的实验已经利用哺乳动物HEK-293和mPCT表达系统来解决该提议的目的。这项提议的新奇在于，在初步研究中发现了新的治疗方式，这些治疗方式可能靶向导致近端RTA的特异性NBC 1突变。从这一提议的结果中获得的数据可以为人类未来治疗这种疾病提供重要依据。本提案中的实验将证实我们的初步发现，定义治疗特定NBC 1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。

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.