PATHOGENESIS OF CALCIUM NEPHROLITHIASIS

这项计划项目拨款涉及特发性草酸钙结石形成的机制。一般的前提是，哺乳动物的肾脏已经进化出抵抗结晶的防御系统，因为它们必须保存水分，同时排泄强制性的钙盐，从而产生不可避免的过饱和。在正常人和形成结石的人中，一个项目专注于定义尿液分子，以防止草酸钙的生长、成核、聚集和肾细胞黏附，并通过肾乳头活组织检查获得，以表征兰德尔斑块的微观解剖、晶体结构以及临床和代谢相关性，这些斑块被认为是锚定乳头状结石的前驱。10多年来，我们培育和研究了一种高钙尿结石形成大鼠，其高钙尿症是由维生素D受体过量引起的。我们的第三个项目关注的是这些动物。因为它们的结石和斑块随着年龄的增长而发展，序列随着年龄的增长而进步，所以可以研究解剖事件的序列，特别是结晶的初始位置。尿液过饱和与结石相关的晶体抑制之间的关系提供了一个易于操作的体内结石形成及其模型。大鼠维生素D载体缺陷为理解该激素系统的调节提供了继续的机会。在我们的第四个项目中，我们提出了大鼠和人类的研究，以明确测试十二指肠中维生素D受体过量导致某些形式的人类高钙尿症的假设。该项目的其他方面涉及骨和甲状旁腺细胞中的受体，以及细胞因子在高钙尿症中调节骨矿物质丢失的作用。在我们的最终项目中，对培养的肾上皮细胞的研究补充和扩大了对人类和大鼠组织以及兰德尔斑块的工作，提供了对细胞如何对晶体做出反应、锚定和摄取晶体的详细了解。

This program project grant concerns mechanisms of idiopathic calcium oxalate stone formation. The general premise is that mammalian kidneys have evolved defenses against crystallization because they must conserve water yet excrete obligatory loads of calcium salts that produce inevitable supersaturations. In normal humans and humans who form stones, one project focuses on defining urine molecules that defend against growth, nucleation, aggregation, and renal cell adhesion of calcium oxalate and obtained by biopsy of renal papillae to characterize microscopic anatomy, crystal structure, and clinical and metabolic correlates of Randall's plaques, which are thought to be a precursor to anchored papillary stones. For over 10 years we have bred and studied a strain of hypercalciuric stone forming rats, whose hypercalciuria arises from an excess of the vitamin D receptor. Our third project focuses on these animals. Because their stones and plaques advance with age, the sequence advance with age, the sequence of anatomical events, especially initial sites of crystallization can be studied. The relationship between urine supersaturations and crystal inhibition in relation to stones affords an easily manipulated in vivo model of stone formation and their. The rat vitamin D vector defect offers continued opportunity for understanding regulation of that hormone system. Rat and human studies are proposed in our fourth project to test definitely the hypothesis that an excess of vitamin D receptor in the duodenum causes some forms of human hypercalciuria. Other aspects of the project concern the receptor in bone and parathyroid cells, and the role of cytokines in mediating bone mineral loss in hypercalciuria. Studies of cultured renal epithelial cells in our final project complement and amplify the work with human and rat tissue and Randall's plaques, offering detailed understanding of how cells react to crystals, anchor and ingest them.