INBORN ERRORS OF A PURINE SALVAGE PATHWAY

描述：Tischfield博士和他的同事们一直在调查 人腺嘌呤磷酸核糖基转移酶的分子和突变基础 （APRT）缺乏症，一种常染色体隐性遗传性嘌呤代谢缺陷， 其在大多数人中产生2，8-二羟基腺嘌呤（DHA）尿石症。 识别纯合子。 根据我们上次更新申请的目的，我们 已经产生了基因靶向的纯合子APRT缺陷小鼠。 这些动物 患有非常严重的早发性DHA肾结石，导致慢性 肾衰竭和许多动物死亡。 这些观察，沿着 生化研究表明，动物是一个忠实的临床和 人类APRT缺陷的遗传模型。 调查人员建议延长 他们对这些老鼠的初步描述， 了解APRT缺乏、嘌呤代谢、DHA肾结石、 一般是尿石症，最后是慢性肾衰竭。 他们有 同样也产生了APRT和HGPRT缺陷的小鼠， 似乎是人类Lesch-Nyhan综合征的模型。 它们打算繁殖 突变体（靶向）APRT进入不同的小鼠品系背景， 定量测定同源菌株特异性差异的程度 尿石症的性质或程度。 这将涉及详细的 形态学、组织学和生化分析 年龄 别嘌呤醇、次黄嘌呤和饮食的治疗作用 修改将被评估。 调查人员还将研究和 在双重缺陷小鼠中抑制从头嘌呤生物合成， 了解其与正常和突变体中嘌呤补救的关系 动物 DHA诱导体外培养肾脏基因表达的研究 上皮细胞和整个肾脏的目的是了解分子 导致肾结石和肾衰竭的遗传过程。

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.