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Alternate Galactose Pathways in GALT-Deficient Mice

GALT 缺陷小鼠的替代半乳糖途径

基本信息

批准号：
6750699
负责人：
STANTON SEGAL
金额：
$ 30.81万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2006-05-31
项目状态：
已结题

项目摘要

Human galactosemia due to deficiency of galactose-1- phosphate uridyltransferase (GALT) is an enigmatic disease. A galactose restricted diet although alleviating neonatal galactose toxicity does not prevent later complications, cognitive impairment, ovarian failure and neurologic ataxia. The inefficacy of diet therapy has mandated a vigorous effort to understand the pathobiochemical basis of the disease in order to develop new therapeutic strategies. The limitations of clinical studies of affected patients prompted the construction of a "knock-out" mouse where a portion of the GALT gene has been deleted thereby eliminating GALT enzyme activity. These animals, however, do not develop the human phenotype and show no evidence of galactose toxicity even when fed galactose. This suggests that the absence of GALT is necessary but not sufficient to produce disease. It appears obvious that factors other than the GALT gene mutation play an important role. The GALT knock-out mouse provides a valuable in vivo test tube to determine the metabolic explanation why these animals do not develop the human phenotype. The aim of this proposal is to examine two possibilities: first, that there is insufficient formation of the metabolite, galactitol, which together with galactose-1-phosphate is necessary to produce the human phenotype; and, second, that there is a robust alternate pathway for galactose disposal. These will be studied by: 1) genetic manipulation to construct a transgenic mouse which expresses human aldose reductase and, when bred with the GALT-deficient animal, will form high levels of galactitol as well as galactose- 1-phosphate and a human phenotype; and, 2) vigorous investigation of metabolic pathways employing isotopic galactose and sophisticated analytic techniques. Great insight into understanding the human condition will be gained by discerning why the GALT knock-out mouse does not exhibit the human galactosemic phenotype.

由于半乳糖-1-磷酸尿苷酰转移酶（GALT）缺乏引起的半乳糖血症是一种神秘的疾病。半乳糖限制饮食虽然可以减轻新生儿半乳糖中毒，但不能预防后期并发症、认知障碍、卵巢功能衰竭和神经性共济失调。饮食疗法的无效性已经要求积极努力了解疾病的病理生物化学基础，以开发新的治疗策略。受影响患者的临床研究的局限性促使构建“敲除”小鼠，其中GALT基因的一部分已被删除，从而消除GALT酶活性。然而，这些动物不发育为人类表型，并且即使在喂食半乳糖时也没有显示半乳糖毒性的证据。这表明缺乏GALT是必要的，但不足以产生疾病。很明显，GALT基因突变以外的因素也起着重要作用。 GALT敲除小鼠提供了一个有价值的体内试管，以确定为什么这些动物不发展人类表型的代谢解释。该提案的目的是研究两种可能性：第一，代谢物半乳糖醇的形成不足，半乳糖醇与半乳糖-1-磷酸一起是产生人类表型所必需的;第二，半乳糖处置存在稳健的替代途径。将由下列人员研究这些问题：1）遗传操作以构建表达人醛糖还原酶的转基因小鼠，并且当与GALT缺陷动物一起繁殖时，将形成高水平的半乳糖醇以及半乳糖-1-磷酸和人表型;和2）采用同位素半乳糖和复杂的分析技术对代谢途径进行有力的研究。通过辨别为什么GALT敲除小鼠不表现出人类半乳糖血症表型，将获得对人类状况的深刻理解。