Hydroxproline Catabolism and Hyperoxaluria

羟脯氨酸分解代谢和高草酸尿症

• 批准号: 7783704
• 负责人: ROSS P HOLMES
• 金额: $ 27.83万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783704
• 关键词: Alanine-glyoxylate aminotransferase; Animals; Benchmarking; Calcium Oxalate; Catabolism; Collagen; Coupled; Data; Defect; Degradation Pathway; Deposition; Detection; Diet; Enzymes; Excretory function; Exhibits; Foundations; Future; Gelatin; Genetic; Glycine; Glycolates; Glyoxylates; Human; Hydroxyproline; Hyperoxaluria; Intravenous infusion procedures; Kidney; Kidney Calculi; Kidney Failure; Knock-out; Knockout Mice; Label; Lead; Metabolic; Metabolism; Modeling; Monitor; Mus; Oxalates; Pathway interactions; Patients; Perfusion; Primary Hyperoxaluria; Production; Proteins; Research; Role; Source; Techniques; Testing; Therapeutic; Tracer; glyoxylate; glyoxylate reductase; human subject; innovation; mouse model; public health relevance; research study; therapeutic target; treatment strategy; urinary

DESCRIPTION (provided by applicant): Primary hyperoxaluria types I and 2 (PH1 and PH2) are characterized by an inability to efficiently metabolize glyoxylate as a consequence of functional defects in alanine-glyoxylate aminotransferase and glyoxylate reductase, respectively. Excessive oxalate synthesis results and may ultimately cause renal failure. To date, there are no therapies that can specifically reduce oxalate synthesis. Hydroxyproline metabolism is the only recognized source of glyoxylate that has been identified to date. We hypothesize that the breakdown of dietary and endogenous hydroxyproline contributes to the bulk of the oxalate synthesized in PH1 and PH2 patients. Confirmation of this hypothesis would suggest that the inhibition of hydroxyproline degradation may be a significant therapeutic opportunity for diminishing endogenous oxalate production in PH patients. As a first step toward testing this hypothesis, we have synthesized homogeneously labeled 13C-hydroxyproline and verified that it can be used to follow the degradation of hydroxyproline to oxalate, glycolate, lactate, and glycine using chromatographic techniques coupled to mass detection. The specific aims of the proposed research are: (1) to quantitate the contribution of hydroxyproline metabolism to endogenous oxalate synthesis in normal human subjects and patients with PH using homogeneously-labeled Hyp, 13C5-hydroxyproline, as a metabolic tracer; (2) to quantitate the contribution of hydroxyproline metabolism to endogenous oxalate synthesis in mouse KO models of PH (Agxt and Grhpr KO) using 13C5-hydroxyproline. Through the quantitation and tracking of the isotopic label within metabolites, we will be able to demonstrate whether or not hydroxyproline degradation contributes to endogenous glycolate, and oxalate synthesis. Moreover, the mouse data will benchmark the contribution of hydroxyproline to urinary glycolate and oxalate in each genetic setting. This latter data will be invaluable for the future testing of therapeutics targeting the unique enzymes of the hydroxyproline degradation pathway. PUBLIC HEALTH RELEVANCE: The synthesis of oxalate, a key component of kidney stones, is influenced by glyoxylate levels. Glyoxylate is produced from hydroxyproline during the normal degradation of collagen within the body and that consumed in the diet. The purpose of this study is to determine whether or not hydroxyproline degradation contributes adversely to the elevated levels of glyoxylate and oxalate production observed in primary hyperoxaluria patients.

描述（由申请人提供）：原发性高尿酸I型和2型（PH 1和PH 2）的特征在于分别由于丙氨酸-乙醛酸氨基转移酶和乙醛酸还原酶的功能缺陷而不能有效代谢乙醛酸。过量的草酸盐合成导致并可能最终导致肾衰竭。迄今为止，还没有可以特异性减少草酸盐合成的疗法。羟脯氨酸代谢是迄今为止已确定的唯一公认的乙醛酸来源。我们推测，膳食和内源性羟脯氨酸的分解有助于PH 1和PH 2患者合成的草酸盐的大部分。这一假设的证实表明，羟脯氨酸降解的抑制可能是减少PH患者内源性草酸盐产生的重要治疗机会。作为检验这一假设的第一步，我们合成了均匀标记的13 C-羟脯氨酸，并验证了它可用于使用色谱技术结合质量检测来跟踪羟脯氨酸降解为草酸盐、乙醇酸盐、乳酸盐和甘氨酸。本研究的具体目的是：（1）用13 C5-羟脯氨酸作为代谢示踪剂，定量测定正常人和PH患者体内羟脯氨酸代谢对内源性草酸合成的贡献;（2）在PH的小鼠KO模型中定量羟脯氨酸代谢对内源性草酸合成的贡献，（Agxt和Grhpr KO）。通过定量和跟踪代谢产物中的同位素标记，我们将能够证明羟脯氨酸降解是否有助于内源性乙醇酸和草酸合成。此外，小鼠数据将基准羟脯氨酸尿乙醇酸和草酸在每个遗传设置的贡献。后者的数据将是非常宝贵的未来测试的治疗靶向羟脯氨酸降解途径的独特酶。 公共卫生相关性：肾结石的关键成分草酸盐的合成受乙醛酸水平的影响。乙醛酸是由羟脯氨酸在体内胶原蛋白的正常降解过程中产生的，并在饮食中消耗。本研究的目的是确定羟脯氨酸降解是否对原发性高尿酸患者中观察到的乙醛酸和草酸盐产生水平升高产生不利影响。