X-LINKED CANINE ATAXIA--MODEL OF SPINOCEREBELLAR ATAXIA

X连锁犬共济失调--脊髓小脑共济失调模型

基本信息

批准号：
2271467
负责人：
DENNIS Paul O'BRIEN
金额：
$ 10.91万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-06-01 至 1999-05-31
项目状态：
已结题

项目摘要

DESCRIPTION: This is a revised proposal designed to investigate the genetic and cellular basis of a recently identified X-linked cerebellar ataxia in English pointer dogs. Affected males hemizygous for X-linked canine ataxia (XCA) show progressive dysmetria and downbeat nystagmus, which is associated with the loss of cerebellar Purkinje cells. XCA thus represents a new model for hereditary cerebellar ataxia in humans. The genetic-analysis components of this proposal include plans to establish a breeding colony of dogs segregating XCA; to confirm the tight linkage of XCA to the androgen-receptor gene on the canine X chromosome; to determine whether there are any defects in the androgen-receptor gene itself that can be correlated with the mutant phenotype; and to identify polymorphisms in flanking X-chromosome loci for the purpose of improving and validating carrier detection. In parallel with these genetic studies, the investigator proposes to characterize the clinical course of the disease in symptomatic affected dogs (usually greater than six months old) and to identify any cerebellar defects associated with their phenotype. Likewise, he proposes to determine the nature of the earliest detectable cerebellar lesions in presymptomatic males that are known to carry the mutant gene by virtue of the genotypes of the androgen- receptor gene and the X-chromosome loci flanking the XCA locus. If the proposed studies funded by the AREA grant indicate that XCA is a good model for more general types of neurodegenerative diseases, a more extensive research program will be proposed that will address the identification of the aberrant gene product involved in the disorder, as well as the analysis of aberrant neurochemical and cellular changes involved in the etiology of the disease. Thus, these studies could then form the basis of a more extensive analysis on possible therapeutic strategies that would have implications for both veterinary and human medicine.

描述：这是一项修订的建议，旨在调查最近确定的X连锁小脑的遗传和细胞基础英国指针狗的共济失调。受影响的男性半合子以x连接犬共济失调（XCA）表现出渐进的障碍性和下beat式眼球震颤，这与小脑Purkinje细胞的丧失有关。 XCA 因此，代表了人类遗传性小脑共济失调的新模型。该提案的遗传分析组成部分包括计划建立一个隔离XCA的狗的繁殖菌落；确认紧身 XCA与犬X染色体上的雄激素受体基因的联系；确定雄激素受体基因中是否存在任何缺陷本身可以与突变表型相关；并确定 X染色体基因座侧面的多态性，以改善并验证载体检测。与这些遗传平行研究，研究者建议表征临床过程有症状受影响的狗的疾病（通常大于六几个月），并确定与他们的小脑缺陷表型。同样，他提议确定最早的本质可检测通过雄激素的基因型携带突变基因受体基因和X染色体基因座侧面XCA基因座。如果是授予地区资助的拟议研究表明XCA是一个很好的更一般类型的神经退行性疾病的模型，更多将提出广泛的研究计划，以解决鉴定涉及该疾病的异常基因产物，以及异常神经化学和细胞变化的分析参与该疾病的病因。因此，这些研究可以构成对可能治疗的更广泛分析的基础对兽医和人类都有影响的策略药品。