CRYSTAL GROWTH INHIBITOR PROTEIN & NEPHROLITHIASIS

晶体生长抑制剂蛋白

• 批准号: 3463891
• 负责人: ELAINE M WORCESTER
• 金额: $ 5.27万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3463891
• 关键词: X ray crystallography; calcification inhibitor; chemical structure function; crystallization; enzyme linked immunosorbent assay; gamma carboxyglutamate; glycoproteins; hormone biosynthesis; hormone regulation /control mechanism; human subject; hypercalciuria; laboratory rabbit; nephrocalcinosis; oxalates; parathyroid hormones; primary hyperoxalurias; protein biosynthesis; protein structure function; urinalysis; vitamin D deficiency; vitamin K deficiency

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.

肾球钙素（NC）是一种钙结合糖蛋白 从人类尿液和人类肾脏组织培养中分离出来， 在体外抑制草酸钙晶体的生长。分子 在从合并的尿液中分离出来的NC中发现了异常 钙石材形成者降低了其对晶体表面的亲和力， 因此，它有能力减慢晶体生长的能力。这种异常包括 γ-羧谷氨酸（GLA）的缺乏。未知是否 NC的结构和功能异常有助于肾脏 某些人的石头形成。该提议的目的是 开始研究NC在石材形成中的作用 石材形成物，并研究调节生产的因素 蛋白质。 在PI先前的研究中，已经使用了蛋白质的抗体 估计正常男性和女性NC的排泄率，以及 将其与尿液抑制草酸钙的能力相关 种子晶体生长系统中的晶体生长。我们的研究也 表明维生素D可能在NC排泄的调节中起作用。 最后，已经从肾脏皮质组织中分离出类似的蛋白质 培养上清液，提供了用于体外研究的模型 调节蛋白质产生。 为了研究某些石材形成异常的可能性 NC分子的量或抑制晶体的能力降低 成长，并了解更多有关异常本身的信息，三种类型 提出了研究； i）具有已知代谢的钙石材形成器 将使用ELISA分析研究缺陷和石材成分 测量NC排泄和晶体生长的测定 抑制活性异常。异常的隔离和研究 蛋白质将完成ii）服用香豆素的患者也将进行研究。 如果缺乏GLA是关键缺陷，这些患者可能会显示 异常类似于石材形成。 iii）研究 蛋白质产生的调节将在细胞培养中进行。 维生素D，PTH，中钙，维生素K缺乏等的影响可以 被评估。 抑制剂异常可能有助于发病机理 石材形成子的子集中的石头。有关特定的知识 异常导致抑制晶体生长和的能力受损 调节该蛋白质产生的因素可能导致 有效的治疗干预措施。