Endogenous Oxalate Synthesis

描述（由申请人提供）：草酸盐的内源性合成增加是罕见遗传性疾病原发性高尿酸的根本原因。这种疾病可能是致命的，由于肾功能衰竭和草酸盐沉积在组织中，特别是如果它在婴儿期出现。内源性草酸盐合成也可能在特发性草酸钙肾结石中起作用，减少合成量可能是一种有效的治疗策略。尽管内源性草酸合成的临床意义，导致其合成的生物合成途径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盐合成的途径，并开发有效降低草酸盐合成的疗法。本研究的具体目标是确定哪些糖和氨基酸有助于草酸盐合成，确定参与的代谢途径，并深入了解这些合成途径的调控。我们的研究将利用最近开发的技术，离子色谱与质量检测（IC/MS），追求这些特定的目标。这项技术将允许使用糖和氨基酸的稳定同位素来确定它们的催化剂是否导致草酸盐的合成。实验将在培养的细胞和注入同位素的人类受试者中进行，以检查这种催化剂。将通过IC/MS和其他程序测定培养基、血液和尿液。将检查激素（主要是胰高血糖素）对这些分解代谢途径的影响，以阐明其调节作用。这些实验将增加我们对内源性草酸盐合成步骤的理解，并可能导致更好的治疗原发性高尿酸血症和草酸钙结石病的治疗方法。原发性高尿酸症是一种罕见的遗传性疾病，可显著改变受影响个体的健康状况，并对他们及其家人造成终身关注。了解体内发生的导致这种疾病的反应可以设计更好的治疗方法，不仅适用于患有这种疾病的人，而且可能适用于那些患有更普遍的草酸钙结石病的人。

DESCRIPTION (provided by applicant): 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.