GLYCOLATE METABOLISM AND KIDNEY OXALATE

乙醇酸代谢和肾草酸盐

基本信息

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
项目类别：
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

项目摘要

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.

概括肾结石，其中最常见的是草酸钙 (CaOx) 结石，影响 7% 至 12% 的肾结石美国人口占所有终末期肾病病例的 3%。尿草酸盐是大约 50% 来自膳食来源，50% 来自通过各种途径内源合成途径。尽管众所周知，大约 80% 的内源性草酸盐是在在肝脏中，草酸产生的途径尚未得到很好的表征。我们的假设是乙醇酸是草酸盐的主要来源，乙醇酸盐的肾脏重吸收导致草酸盐的肾脏合成。确定乙醇酸盐在肾脏和肝脏草酸盐合成中的作用对于患有以下疾病的患者具有重要意义：遗传性疾病原发性高草酸尿症 (PH)，其中内源性草酸生成过多导致严重的复发性氧化钙肾结石。建立这些途径可能会导致新的治疗方法来抑制乙醇酸氧化，导致草酸产量减少。该提案将 1) 测试乙醇酸的代谢是否有助于内源草酸的合成执行启动、稳定状态、连续静脉输注乙醇酸稳定同位素、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肾小管细胞 3) 使用离体大鼠肾灌注测定乙醇酸的肾重吸收和代谢。这羟酸氧化酶 2 (HAO2) 和乙醛酸还原酶 (GR) 的作用将在此转换的上下文。与此提案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独立组织草酸盐代谢及其相关临床疾病领域的研究计划，包括原发性高草酸尿症。