TISSUE-CRYSTAL INTERACTION CA OXALATE NEPHROLITHIASIS

尿石症是一种重要的泌尿系统疾病，困扰着很大一部分美国人，每年花费约23.9亿美元。近三分之二的尿路结石含有草酸钙。首次发病后10年内结石复发的几率超过60%。为了减少复发的可能性，有必要了解结石形成的机制，并确定结石起始的尿液标志物。该项目旨在了解所涉及的过程和识别尿液标志物，这些标志物可用于确定肾结石的发病。我们的假设是，草酸钙结石的形成涉及一系列事件，从高草酸尿开始。中度高血氧刺激诱导结晶调节剂如骨桥蛋白的产生增加，骨桥蛋白与钙以及钙晶体相互作用，并促进钙晶体从肾小管中移除。然而，高浓度草酸会损伤肾上皮细胞。这种损伤通过提供晶体成核的底物、晶体聚集的媒介和创造晶体粘附在肾上皮细胞上的位点，促进了晶体的形成和它们在肾小管内的保留。受损细胞产生的结晶调节剂可能异常或功能不足。这种非典型调制剂的产生可以表明结石形成级联的开始。我们想用1来检验这个假设。草酸钙肾结石动物模型1例；细胞培养实验。在动物模型中，雄性大鼠可诱导高血氧性尿。细胞培养实验中肾上皮细胞；MDCK和LLC-PK1暴露于草酸盐和草酸钙晶体中。我们可以在动物模型中跟踪肾结石的各种事件，猫在细胞培养中探索肾上皮细胞暴露于草酸盐和草酸钙晶体的结果。

Urolithiasis is a significant urological disease afflicting a large percentage of US population costing approximately 2.39 billion dollars/year. Nearly two-thirds of the urinary stones contain calcium oxalate. Chances of stone recurrence within 10 years of the first episode are over 60 percent. To reduce the likelihood of recurrence it is necessary to understand the mechanisms involved in stone formation and to determine urinary markers of stone initiation. This project is aimed towards developing an understanding of the processes involved and identification of urinary markers which can be utilized to determine the onset of nephrolithiasis. It is our hypothesis that calcium oxalate stone formation involves a cascade of events which starts with hyperoxaluria. A moderate hyperoxaluric challenge induces increased production of crystallization modulators such as osteopontin which interact with calcium as well as the calcific crystals and facilitate their removal from the renal tubules. Significantly high level of oxalate however, injures the renal epithelial cells. The injury results in promotion of crystal formation and their retention within the renal tubules by providing substrates for crystal nucleation, agents for crystal aggregation and by creating sites for crystal adherence to the renal epithelial cells. Crystallization modulators produced by the injured cells maybe abnormal and/or functionally inadequate. Production of such atypical modulators can indicate initiation of the stone forming cascade. We want to test this hypothesis using, 1. an animal model of calcium oxalate nephrolithiasis and, 2. cell culture experiments. In the animal model hyperoxaluria is induced in male rats. In cell culture experiments renal epithelial cell; MDCK and LLC-PK1 are exposed to oxalate and calcium oxalate crystals. We can follow various events of nephrolithiasis in the animal model and cats explore the outcome of renal epithelial cell exposure to oxalate and calcium oxalate crystals in the cell cultures.