GLYCOLATE METABOLISM AND KIDNEY OXALATE

总结 肾结石，其中最常见的是草酸钙（CaOx）结石，影响7至12%的 美国人口占所有终末期肾病病例的3%。尿草酸盐 来源于大约50%的膳食来源和50%来自内源性合成，通过各种 途径。虽然已经确定大约80%的内源性草酸盐是在体内产生的， 在肝脏中，草酸盐产生的途径还没有很好的表征。我们的假设是乙醇酸是 是草酸盐的主要来源，肾对乙醇酸盐的重吸收导致肾合成草酸盐。 确定乙醇酸盐在肾脏和肝脏合成草酸盐中的作用对患有 一种遗传性疾病原发性高草酸尿症（PH），其中内源性草酸盐产生过多导致 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来抑制 乙醇酸盐氧化，导致草酸盐产生减少。 该提案将1）通过以下方式测试乙醇酸代谢是否有助于内源性草酸盐合成： 进行乙醇酸盐的稳定同位素、碳- 13乙醇酸，在健康志愿者中。2)检验乙醇酸在近端代谢为草酸的假设 使用人近端小管细胞系和新鲜分离的人近端小管片段的小管细胞 和3）使用离体大鼠肾脏灌注测定乙醇酸的肾脏重吸收和代谢。的 酶羟酸氧化酶2（HAO 2）和乙醛酸还原酶（GR）的作用将在下文中定义。 这一转变的背景。 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 来实现她的目标这位候选人的长期目标是领导一个强大的独立派 草酸盐代谢领域的研究计划和与之相关的临床疾病，包括 原发性高尿酸血症

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.