GLYCOLATE METABOLISM AND KIDNEY OXALATE

摘要 肾结石，其中最常见的是草酸钙(CaOx)结石，影响7%到12%的 占所有终末期肾病病例的3%。尿草酸是 来自大约50%的饮食来源，50%来自内源合成，通过各种 小路。尽管众所周知，大约80%的内源草酸是在 肝脏，草酸产生的途径还没有得到很好的描述。我们的假设是乙醇酸盐是 草酸的一个主要来源，而且乙醇酸的肾脏重吸收导致肾脏合成草酸。 确定乙醇酸在肾脏和肝脏草酸合成中的作用对患有 遗传性疾病原发性高草酸尿症(PH)，内源性草酸产生过多导致 严重复发的CaOx肾结石。建立这些途径可能会导致新的治疗方法 乙醇酸盐氧化，导致草酸盐产量减少。 这项提议将1)测试乙醇酸的代谢是否通过以下方式促进内源草酸的合成 进行预置的、稳定状态的、持续静脉输注乙醇酸稳定同位素碳- 13乙醇酸盐，在健康志愿者中。2)检验乙醇酸在近端代谢为草酸的假设 应用人近端小管细胞系和新鲜分离的人近端小管片段的肾小管细胞 3)用大鼠离体肾灌流测定乙醇酸在肾脏的重吸收和代谢。这个 羟酸氧化酶2(HaO2)和乙醛酸还原酶(GR)的作用将在 此转换的上下文。 与此建议书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水平 这些都是实现她的目标所必需的。候选人的长期目标是领导一个强大的无党派人士 草酸代谢和与之相关的临床疾病领域的研究方案，包括 原发的高草酸尿症。

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.