PATHOGENESIS OF HUMAN NEPHROLITHIASIS

该项目涉及抑制人类肾脏中晶体形成的分子。形成结石的男性与正常男性的不同之处在于产生的尿液在减缓草酸钙晶体生长方面效果较差，并且其中草酸钙和磷酸钙的过饱和度与产生结晶所需的过饱和度之间的距离（亚稳性上限，乌尔姆）减小。在女性中进行一项平行研究，以确定其结石机制是否与男性不同，并在我们已经描述的男性结石形成者的家庭成员中进行研究，以确定生长抑制和乌尔姆至过饱和距离的降低是否具有家族性。与项目2合作，我们建议确定是否减少抑制与兰德尔的斑块数量和表面积相关。考虑到男性生长抑制缺陷，我们建议通过对异常钙颗粒蛋白分子大小分布和特异性生长抑制活性的初步观察，以及通过对比患者和对照透析尿液分子对草酸钙晶体产生同等程度生长抑制的蛋白质，来确定相关分子。我们将探讨尿液中的结晶消耗高亲和力抑制剂，降低其可用性的可能性，通过确定EDTA溶解对尿液分子生长抑制的影响。最后，我们计划进行类似的实验，通过对比来自患者和正常人的分子与草酸钙和磷酸钙晶体的结合，来鉴定导致乌尔姆至过饱和距离减小的分子，所述草酸钙和磷酸钙晶体是当他们的尿液过饱和度在体外升高到乌尔姆以上时产生的。我们还将探讨尿焦磷酸盐减少或尿柠檬酸盐和尿pH值之间的异常关系可能导致患者乌尔姆减少的可能性。

This project concerns the molecules that inhibit formation of crystals in human kidneys. Males who form stones differ from normal males in producing urine less effective in slowing the growth of calcium oxalate crystals, and in which the distance between supersaturation and the supersaturation needed to produce crystallization (upper limit of metastability, ULM) is reduced for both calcium oxalate and calcium phosphate. A parallel study is proposed in women, to determine if their mechanisms of stones differ from those in men, and in family members of the male stone formers we have already characterized, to determine if reduced growth inhibition and ULM to supersaturation distance is familial. In collaboration with Project 2, we propose to determine if reduced inhibitions correlate with Randall's plaque number and surface area. Given the male growth inhibition defect, we propose to identify molecules responsible by pursuing our initial observation of aberrant calgranulin molecular size distribution and specific growth inhibition activity, and by contrasting proteins bound to calcium oxalate crystals brought to equivalent degrees of growth inhibition by patient and control dialyzed urine molecules. We will explore the possibility that crystallization in urine consumes high affinity inhibitors reducing their availability, by determining the effects of EDTA dissolution on growth inhibition by urine molecules. Finally, we plan similar experiments to identify molecules responsible for the reduced ULM to supersaturation distance by contrasting molecules from patients and normals bound to the calcium oxalate and calcium phosphate crystals produced as their urine supersaturation is raised above the ULM in vitro. We will also explore the possibility that reduced urine pyrophosphate or an abnormal relationship between urine citrate and urine pH may contribute to the reduced ULM in patients.