INBORN ERRORS OF A PURINE SALVAGE PATHWAY

嘌呤挽救途径的先天性错误

• 批准号: 2608413
• 负责人: JAY Arnold TISCHFIELD
• 金额: $ 26.37万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2608413
• 关键词: Lesch Nyhan syndrome; adenine phosphoribosyltransferase; allopurinol; clinical research; diet therapy; enzyme activity; enzyme deficiency; family genetics; gene mutation; gene targeting; genetic mapping; genetically modified animals; human genetic material tag; human subject; hypoxanthines; inborn metabolism disorder; laboratory mouse; nephrolithiasis; nonhuman therapy evaluation; nutrition related tag; purine /pyrimidine metabolism disorder; sex hormones; tissue /cell culture; urinalysis; urinary calculi

DESCRIPTION: Dr. Tischfield and his colleagues have been investigating the molecular and mutational basis for human adenine phosphoribosyl-transferase (APRT) deficiency, an autosomal recessive inborn error of purine metabolism, which produces 2,8-dihydroxyadenine (DHA) urolithiasis in the majority of recognized homozygotes. Per the aims of our last renewal application, we have produced gene-targeted, homozygous, APRT-deficient mice. These animals have very severe and early onset DHA renal lithiasis which leads to chronic renal failure and death in many animals. These observations, along with biochemical studies, indicate that the animals are a faithful clinical and genetic model of human APRT deficiency. The investigators propose to extend their very preliminary characterization of these mice in an effort to better understand APRT deficiency, purine metabolism, DHA renal lithiasis, urolithiasis in general, and, ultimately, chronic renal failure. They have also produced mice that are both APRT and HGPRT-deficient which do not appear to be a model for human Lesch-Nyhan syndrome. They propose to breed the mutant (targeted) APRT into different mouse strain backgrounds and quantitatively determine the extent of congenic strain specific differences in the nature or degree of urolithiasis. This will involve detailed morphological, histological, and biochemical analysis of mice of different ages. The therapeutic effects of allopurinol, hypoxanthine, and diet modifications will be evaluated. The investigators will also study and inhibit de novo purine biosynthesis in doubly deficient mice to better understand its relationship with purine salvage in normal and mutant animals. A study of DHA-induced gene expression in cultured kidney epithelial cells and whole kidneys is aimed at understanding molecular genetic processes that lead to nephrolithiasis and kidney failure.

描述：Tischfield博士及其同事一直在调查 人腺嘌呤磷酸蛋白基转移酶的分子和突变基础 （APRT）缺乏素，一种常染色体隐性天生的嘌呤代谢错误， 在大多数的 公认的纯合子。 根据我们上次续签应用的目的，我们 已经产生了靶向基因的，纯合，APRT缺陷的小鼠。 这些动物 患有非常严重的早期发作DHA肾脏岩性，导致慢性 许多动物的肾衰竭和死亡。 这些观察以及 生化研究，表明动物是忠实的临床和 人类APRT缺乏的遗传模型。 调查人员建议扩展 它们对这些小鼠的初步特征是为了改善 了解APRT缺乏症，嘌呤代谢，DHA肾脏岩性， 一般而言，尿石病，最终是慢性肾衰竭。 他们有 还产生了既有APRT和HGPRT缺乏剂的小鼠 似乎是人类Lesch-Nyhan综合征的模型。 他们建议繁殖 突变体（靶向）APRT进入不同的小鼠应变背景和 定量确定先天性应变特异性差异的程度 在尿石病的性质或程度上。 这将涉及详细 小鼠的形态学，组织学和生化分析 年龄。 别嘌呤醇，甲明和饮食的治疗作用 将评估修改。 调查人员还将学习和 抑制双重小鼠中的从头嘌呤生物合成以更好 了解其与普通和突变体中嘌呤救助的关系 动物。 DHA诱导的培养肾脏基因表达的研究 上皮细胞和整个肾脏旨在理解分子 导致肾物石病和肾衰竭的遗传过程。