GLYCOLATE METABOLISM AND KIDNEY OXALATE

乙醇酸代谢和肾草酸盐

• 批准号: 10242133
• 负责人: Sonia Fargue
• 金额: $ 15.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2023-06-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242133
• 关键词: Address; Affect; Alanine-glyoxylate aminotransferase; American; Analytical Chemistry; Animals; Calcium Oxalate; Carbon; Cell Line; Cells; Clinical; Clinical Trials; Continuous Intravenous Infusion; Crystallization; Data; Diet; Disease; End stage renal failure; Ensure; Enzymes; Excretory function; Extrahepatic; Fasting; Glycolates; Goals; Healthcare; Hepatic; Hereditary Disease; Human; Hydroxy Acids; Inflammation; Infusion procedures; Intravenous; Kidney; Kidney Calculi; Knowledge; Label; Lactate Dehydrogenase; Lactoylglutathione Lyase; Lead; Liver; Mentors; Metabolic; Metabolic Pathway; Metabolism; Oxalates; Oxidases; Oxidative Stress; Pathway interactions; Patients; Perfusion; Population; Primary Hyperoxaluria; Production; Rattus; Recurrence; Reporting; Research; Role; Source; Specificity; Testing; Tissues; Training; Tubular formation; United States; Urine; Woman; Work; care burden; dietary; glyoxylate reductase; healthy volunteer; human subject; kidney cell; kidney cortex; men; oxidation; programs; skills; stable isotope

SUMMARY Kidney stones, of which the most common are calcium oxalate (CaOx) stones, affect 7 to 12% of the United States population and are responsible for 3% of all end-stage renal disease cases. Urine oxalate is derived from approximately 50% dietary sources and 50% from endogenous synthesis through various pathways. Though it is well established that approximately 80% of the endogenous oxalate is produced in the liver, the pathways for oxalate production are not well characterized. Our hypothesis is that glycolate is a major source of oxalate and that the renal reabsorption of glycolate leads to renal synthesis of oxalate. Establishing the role of glycolate in renal and liver synthesis of oxalate has implications for patients with the hereditary disease primary hyperoxaluria (PH), in which excessive endogenous oxalate production leads to severe recurrent CaOx kidney stones. Establishing these pathways could lead to new treatments to inhibit glycolate oxidation, resulting in reduced oxalate production. This proposal will 1) test if the metabolism of glycolate contributes to endogenous oxalate synthesis by performing primed, steady state, continuous intravenous infusions of the stable isotope of glycolate, carbon- 13 glycolate, in healthy volunteers. 2) test the hypothesis that glycolate is metabolized to oxalate in proximal tubule cells using a human proximal tubule cell line and freshly isolated human proximal tubule fragments and 3) determine renal reabsorption and metabolism of glycolate using isolated rat kidney perfusions. The roles of the enzyme hydroxyacid oxidase 2 (HAO2) and glyoxylate reductase (GR) will be defined in the context of this conversion. The mentoring team and training plan associated with this proposal will ensure that the candidate reaches the level of expertise in analytical chemistry, metabolic research, and human and animal studies that are necessary to meet her goals. The candidate's long-term objective is to lead a strong independent research program in the field of oxalate metabolism and the clinical disorders associated with it, including the primary hyperoxalurias.

概括 最常见的肾结石是草酸钙（Caox）石头，影响了7％至12％ 美国人口，占所有终末期肾脏疾病病例的3％。草酸盐是尿液 通过各种 途径。尽管已经很好地确定，大约80％的内源草酸盐是在 肝脏，草酸盐产生的途径没有很好地表征。我们的假设是糖酸是 草酸盐的主要来源和乙醇酸盐的肾脏重吸收会导致草酸盐的肾脏合成。 确定乙醇酸在草酸盐合成中的作用，对患有 遗传性疾病原发性高黄油（pH），其中过量的内源草酸盐产生导致 严重的复发性CAOX肾结石。建立这些途径可能会导致新的治疗方法抑制 糖基氧化，导致草酸盐产生降低。 该提议将测试糖基酸的代谢是否有助于通过 对乙酸，碳 - 13个乙醇酸酯，在健康的志愿者中。 2）检验乙醇酸在近端中的草酸盐代谢的假设 小管细胞使用人近端小管细胞系和新鲜分离的人近端小管片段 3）使用分离的大鼠肾脏灌注来确定糖基糖酸盐的肾脏重吸收和代谢。这 羟基酸氧化酶2（HAO2）和乙二醇还原酶（GR）的作用将定义在 这种转换的上下文。 与该建议相关的指导团队和培训计划将确保候选人 达到分析化学，代谢研究以及人类和动物研究的专业知识水平 实现她的目标是必要的。候选人的长期目标是领导一个强大的独立 草酸盐代谢领域的研究计划以及与之相关的临床障碍 原发性高氧化盐。