PATHOGENESIS OF HUMAN CALCIUM NEPHROLITHIASIS

人类钙肾结石的发病机制

• 批准号: 3733344
• 负责人: FREDRIC L COE
• 金额: --
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3733344
• 关键词: 1,25 dihydroxycholecalciferol; calcium; crystallization; dietary control; gastrointestinal nutrient absorption; glycoproteins; human subject; hypercalciuria; inhibitor /antagonist; kidney cell; monocyte; nephrolithiasis; osteocalcin; parathyroid hormones; pathologic process; steroid hormone receptor; tissue /cell culture; urine

This project will test three hypotheses. Two concern urine inhibitors of crystallization, in humans and our inbred IH rats; the third concerns human Idiopathic Hypercalciuria (IH). Hypothesis 1): Normal urine inhibits crystallization and renal cell attachment of crystals (with Project 4, Toback); we hypothesize that reduced inhibition by whole urine (Specific Aim 1) and by three specific proteins, nephrocalcin (NC), Tamm-Horsfall protein (THP), and Uropontin (UP) (Specific Aim 2), contribute to human calcium nephrolithiasis (NL). Hypothesis 2): In rats inbred for IH (Project 2, Specific Aim 2), some but not all form calcium stones; we hypothesize that reduced inhibition by urine and the three specific proteins promote stones in some of these animals (Specific Aim 3). Planned methods for hypotheses 1 and 2 include assays for inhibition of COM nucleation, growth, aggregation, and crystal attachment to renal cells applied to mixed urine proteins (Specific Aim 1) and the same assays applied to NC, THP and UP purified from human urines (Specific Aim 2) and urine from IH rats (Specific Aim 3). Hypothesis 3): In IH rats, increased Vitamin D receptor mediates intestinal calcium hyperabsorption; we hypothesize that some human IH patients and their families exhibit vitamin D receptor (VDR) abnormalities that cause intestinal calcium hyperabsorption, hypercalciuria and stones, independent of high serum calcitriol levels, and that elevated VDR levels may be inherited. Planned measurements include: 1) VDR levels in circulating monocytes (with Project 1, Favus); 2) response of monocyte VDR to calcitriol and low calcium diet; 3) calcium absorption using oral calcium load and metabolic balance; 4) serum calcitriol, osteocalcin, and PTH levels, and urine calcium excretion, during low calcium diet or oral calcitriol challenge, in monocyte VDR levels; 5) and family studies of patients found to harbor elevated monocyte VDR levels.

该项目将检验三个假设。两种关注的尿液抑制剂 结晶，在人类和我们的近交IH大鼠中；第三个问题 人特发性高钙尿液（IH）。假设1）：正常尿液抑制 晶体的结晶和肾细胞附着（项目4， toback）;我们假设整个尿液降低了抑制作用（具体 AIM 1）和三种特定蛋白质，肾红细胞素（NC），Tamm-Horsfall 蛋白质（THP）和乌罗泊汀（UP）（特定目标2）有助于人类 钙肾石器（NL）。假设2）：在IH的大鼠中 （项目2，特定目标2），有些但不是全部形成钙石；我们 假设尿液和三个特异性的抑制作用减少了 蛋白质在其中一些动物中促进石头（特定目的3）。计划 假设1和2的方法包括抑制COM的测定法 成核，生长，聚集和晶体附着肾细胞 应用于混合尿蛋白（特定目标1）和相同的测定 应用于NC，THP并从人类尿液中纯化（特定目的2）和 IH大鼠的尿液（特定目标3）。假设3）：在IH大鼠中，增加 维生素D受体介导肠道钙高吸收。我们 假设某些人IH患者及其家人表现出维生素 D受体（VDR）异常引起肠钙 高吸收，高钙和石头，与高血清无关 骨化三醇水平以及升高的VDR水平可以遗传。计划 测量包括：1）循环单核细胞中的VDR水平（带有项目 1，Favus）; 2）单核细胞VDR对钙三醇和低钙饮食的反应； 3）使用口服钙负荷和代谢平衡的钙吸收； 4） 血清钙三醇，骨钙素和PTH水平和尿钙 排泄，在低钙饮食或口服钙三醇挑战期间，在 单核VDR水平； 5）和发现藏有的患者的家庭研究 单核VDR水平升高。