Endogenous Oxalate Synthesis

描述（由申请人提供）：草酸盐内源性合成增加是罕见遗传性疾病原发性高草酸尿的潜在原因。这种疾病可能是致命的，由于肾功能衰竭和草酸沉积在组织中，特别是如果它表现在婴儿期。内源性草酸合成也可能在特发性草酸钙肾结石中发挥作用，减少草酸钙的合成量可能是一种有效的治疗策略。尽管内源性草酸合成具有临床意义，但导致其合成的生物合成途径在很大程度上是未知的。该研究项目的长期目标是确定草酸合成的途径，并开发有效减少草酸合成的疗法。本提案的具体目标是确定哪些糖和氨基酸有助于草酸盐的合成，确定所涉及的代谢途径，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，离子色谱联用质量检测（IC/MS），以实现这些具体目标。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分解代谢是否导致草酸合成。实验将在培养细胞和注入同位素的人类受试者中进行，以检查这种分解代谢。培养基，血液和尿液将通过IC/MS和其他程序进行检测。激素，主要是胰高血糖素，对这些分解代谢途径的影响将被检查以阐明其调节。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方法来治疗原发性高草酸血症和草酸钙结石疾病。原发性高草酸尿是一种罕见的遗传性疾病，可显著改变患者的健康状况，并引起患者及其家人的终生关注。了解体内发生的导致这种疾病的反应可以设计出更好的治疗方法，不仅适用于患有这种疾病的人，也可能适用于那些患有更为普遍的草酸钙结石的人。

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.