CRYSTAL GROWTH INHIBITOR PROTEIN & NEPHROLITHIASIS

肾钙素(NC)是一种钙结合糖蛋白，已被 从人尿和人肾组织培养中分离出来， 抑制草酸钙晶体的体外生长。分子 从混合尿液中分离出的NC中发现异常 钙结石的形成降低了它对晶体表面的亲和力， 因此它能够减缓晶体的生长。此异常包括 伽玛-羧基谷氨酸(GLA)缺乏。目前还不清楚 NC的结构和功能异常与肾的关系 某些个体的结石形成。这项提议的目标是 开始研究NC在个体钙结石形成中的作用 并研究调控石材生产的因素。 蛋白。 在PI之前的研究中，已经使用了针对该蛋白质的抗体 估计正常男女的NC排泄率，并 这与尿液抑制草酸钙的能力有关 籽晶生长系统中的晶体生长。我们的研究还包括 提示维生素D可能在NC的排泄调节中起作用。 最后，从肾皮质组织中分离出了类似的蛋白质。 培养上清，为体外研究提供了一个模型。 蛋白质生产的调控。 调查一些造石者制造反常的可能性 NC分子，在数量上或在抑制晶体的能力上减少 增长，并更多地了解异常本身，有三种类型 1)已知代谢的钙结石形成者 缺陷和结石成分将使用ELISA法进行研究，以 测量NC排泄量，并对晶体生长进行检测 抑制活性异常。异常信号的分离与研究 蛋白质将被做II)服用香豆素的患者也将被研究。 如果缺乏GLA是关键缺陷，这些患者可能会表现出 类似于铸石者的异常。三)研究 蛋白质生产的调节将在细胞培养中进行。 维生素D、甲状旁腺素、中钙、维生素K缺乏等影响可 被评估。 很可能是抑制物的异常参与了发病机制。 成石者的子集中的石头。关于特定问题的知识 导致抑制晶体生长能力受损的异常现象 调节这种蛋白质的产生的因素可能会导致 有效的治疗干预。

Nephrocalcin (NC) is a calcium-binding glycoprotein that has been isolated from human urine and human kidney tissue culture, and that inhibits growth of the calcium oxalate crystals in vitro. Molecular abnormalities have been found in NC isolated from the pooled urine of calcium stone formers, which decrease its affinity for crystal surface, and thus its ability to slow crystal growth. This abnormality includes a deficiency of gamma-carboxglutamic acid (GLA). It is unknown whether abnormalities in the structure and function of NC contribute to kidney stone formation in certain individuals. The goal of this proposal is to begin to study the role of NC in stone-formation in individual calcium stone-formers, and to study the factors that regulate production of the protein. In previous studies by the PI, antibodies to the protein have been used to estimate excretion rates of NC in normal men and women, and to correlate this with the ability of the urine to inhibit calcium oxalate crystal growth in a seeded crystal growth system. Our studies have also shown that Vitamin D may play a role in regulation of NC excretion. Finally a similar protein has been isolated from kidney cortical tissue culture supernatants, providing a model for in vitro studies of regulation of protein production. To investigate the possibility that some stone-formers make an abnormal NC molecule, decreased either in amount or in ability to inhibit crystal growth, and to learn more about the abnormalities themselves, three types of studies are proposed; I) Calcium stone formers with known metabolic defects and stone composition will be studied using ELISA assay to measure NC excretion, and assays of crystal growth to detect abnormalities in inhibitory activity. Isolation and study of abnormal proteins will be done II) Patients taking coumadin will also be studied. If lack of GLA is the crucial defect, these patients may display abnormalities similar to those of stone-formers. III)Studies of regulation of protein production will be carried out in cell culture. Effect of vitamin D, PTH, medium calcium, vitamin K deficiency, etc. can be assessed. It is likely that inhibitor abnormalities contribute to the pathogenesis of stones in a subset of stone-formers. Knowledge about the specific abnormalities that lead to impaired ability to inhibit crystal growth and of the factors that regulate production of this protein may lead to effective therapeutic interventions.