NBC1 and Proximal RTA: Pathogenesis and Treatment

描述（申请人提供）：肾小管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，扰乱各器官系统的功能。肾小管酸中毒患者通常有肾外表现，不能有效地治疗基础疗法。不幸的是，我们目前缺乏针对近端小管和肾外组织潜在运输异常的特异性治疗。我们对遗传形式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体突变的特定治疗方法提供了独特的机会。本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。遗传性肾小管近端酸中毒是由SLC4A4电致碳酸氢钠共转运体NBC1突变引起的。NBC1负责介导近端小管基底外侧碳酸氢盐的吸收和包括胰腺、眼和脑在内的外肾组织的碳酸氢盐运输。鉴于已知的错义、无义和缺失突变会降低这种疾病的共转运蛋白功能，NBC1转运蛋白突变给治疗带来了挑战。在初步实验中，我们已经开始填补目前对突变共转运体的生物合成、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表达系统来解决这一建议的目的。该建议的新颖之处在于，在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。本研究结果所获得的数据可为今后治疗人类本病提供重要依据。本提案中的实验将证实我们的初步发现，确定治疗特定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肾近端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.