Endogenous Oxalate Synthesis

草酸盐的内源性合成增加是这种罕见遗传病的根本原因， 原发性高尿酸血症由于肾衰竭和组织中的草酸盐沉积，这种疾病可能是致命的， 尤其是在婴儿期出现的内源性草酸盐合成也可能在特发性 减少草酸钙肾结石的合成是有效的治疗方法 战略尽管内源性草酸盐合成具有临床意义， 导致其合成方法在很大程度上是未知的。本研究项目的长期目标是确定 参与草酸合成的途径，并开发有效减少草酸合成的疗法。 这项建议的目的是确定哪些糖和氨基酸有助于草酸盐 合成，以确定所涉及的代谢途径，并深入了解这些调节 合成途径。我们的研究将利用最近开发的技术，离子色谱耦合 与质量检测（IC/MS），追求这些特定的目标。这种技术将允许使用稳定的 糖和氨基酸的同位素，以确定它们的催化剂是否导致草酸合成。 实验将在培养的细胞和注入同位素的人类受试者中进行，以检查这一点。 猫将通过IC/MS和其他程序测定培养基、血液和尿液。的影响 将检查激素，主要是胰高血糖素对这些分解代谢途径的作用，以阐明它们的调节。 这些实验将增加我们对内源性草酸合成所涉及的步骤的理解 并可能导致更好的治疗方法来治疗患有原发性高尿酸和草酸钙的个体 结石病 原发性高尿酸症是一种罕见的遗传性疾病，可以显着改变健康的影响， 对他们和他们的家人造成终身的关注。了解发生的反应 在体内引起这种疾病可能会导致更好的治疗设计，不仅对个人， 这种疾病，但可能为那些谁患有更普遍的草酸钙结石病。

An increased endogenous synthesis of oxalate is the underlying cause of the rare genetic disease, primary hyperoxaluria. This disease can be fatal due to renal failure and oxalate deposition in tissues, particularly if it manifests during infancy. Endogenous oxalate synthesis may also play a role in idiopathic calcium oxalate nephrolithiasis and decreasing the amount synthesized could be an effective therapeutic strategy. Despite the clinical significance of endogenous oxalate synthesis, the biosynthetic pathways that lead to its synthesis are largely unknown. The long-term goals of this research project are to define the pathways involved in oxalate synthesis and to develop therapies that will effectively reduce it. The specific aims of this proposal have been developed to determine which sugars and amino acids contribute to oxalate synthesis, to identify the metabolic pathways involved, and to gain an insight into the regulation of these synthetic pathways. Our research will utilize a recently developed technique, ion chromatography coupled with mass detection (IC/MS), to pursue these specific aims. This technique will allow the use of stable isotopes of sugars and amino acids to determine whether their catabolism leads to oxalate synthesis. Experiments will be conducted in cultured cells and in human subjects infused with isotopes to examine this catabolism. Culture media, blood and urine will be assayed by IC/MS and other procedures. The effects of hormones, principally glucagon, on these catabolic pathways will be examined to elucidate their regulation. These experiments will increase our understanding of the steps involved in endogenous oxalate synthesis and may lead to better therapies to treat individuals with the primary hyperoxalurias and with calcium oxalate stone disease. Primary hyperoxaluria is a rare genetic disease that can significantly alter the health of affected individuals and cause a life-long concern for them and their families. Understanding the reactions that occur in the body to cause this disease could lead to the design of better treatments, not only for individuals with this disease, but possibly for those who suffer from the much more prevalent calcium oxalate stone disease.