GENETIC MODEL OF HUNTINGTONS DISEASE

该项目的最终目标是了解原因， 结果的表达扩大（CAG）n三联重复在 亨廷顿病基因，并确定这些知识是否可以 应用于开发治疗该疾病的有效模式。是 不清楚这种三核苷酸重复序列的扩增如何导致 一部分神经元的过早死亡而且 正常IT15基因编码蛋白的功能特征 必须定义。人类并不是一个可操纵的实验系统 在这些问题上可以探索，目前还没有遗传学 HD动物模型因此，我们计划利用 在将外源基因导入小鼠方面取得的进展 创造一批转基因小鼠， 三个关键问题，（CAG）n突变的不稳定性， 在小鼠中，正常HD等位基因的功能通过无效的表型 突变，以及由扩增的（CAG）n重复序列产生的表型， 在引入的人基因中或适当地定位在内源性基因中， 小鼠基因表达人HD构建体的小鼠和改变的小鼠 将培育同源物以建立HD遗传动物模型， 将进行详细分析。 这个项目是一个具有挑战性的事业，像以前一样， HD基因的连锁作图和随后的克隆的成功， 对HD研究的各个方面都有革命性的影响。如果鼠标 模型表达了显著的神经病理学，这将允许更多的 详细分析的解剖和生化影响的 扩增的（CAG）n IT15三联体重复序列，其表达的遗传学，以及 它与神经元死亡的兴奋毒素假说的关系，而 提供了一个精确的系统，其中治疗方法可以 测试.然而，即使表达HD基因的小鼠不能表达任何 异常，他们将值得继续研究，以确定基础， 他们缺乏对HD的易感性，这可能提供了一个线索， 人的潜在治疗。

The ultimate goals of this project are to understand the causes and consequences of the expression of the expanded (CAG)n triplet repeat in the Huntington's disease gene and to determine whether this knowledge can be applied to develop an effective mode of therapy for the disorder. It is not clear how expansion of this trinucleotide repeat sequence can lead to the premature death of a specific subset of neurons. Furthermore, the functional characteristics of the protein encoded by the normal IT15 gene must be defined. Man does not constitute a manipulable experimental system in which these issues can be explored and there is presently no genetic animal model of HD. Consequently, we plan to take advantage of the advances which have been made in introducing foreign genes into the mouse to create a collection of transgenic mice that will permit the exploration of three critical issues, the instability of the (CAG)n mutation ,in the mouse, the function of the normal HD allele via the phenotype of a null mutation, and the phenotype produced by the expanded (CAG)n repeat, either in an introduced human gene or appropriately positioned in the endogenous mouse gene. Mice that express human HD constructs and the altered mouse homologue will be bred to establish a genetic animal model of HD which will be subjected to detailed analysis. This project is a challenging undertaking which, like the previous successes in linkage mapping and subsequent cloning of the HD gene, could have a revolutionary impact on all aspects of HD research. If the mouse model expresses significant neuropathology, it would permit a much more detailed analysis of the anatomical and biochemical effects of the expanded (CAG)n IT15 triplet repeat, the genetics of its expression, and its relationship to the excitotoxin hypothesis of neuronal death, while providing an accurate system in which therapeutic approaches could be tested. However, even if mice expressing the HD gene fail to express any abnormality, they will merit continued study to determine the basis for their lack of susceptibility to HD, which might provide a clue to a potential treatment in man.