GENETIC MODEL OF HUNTINGTONS DISEASE

这个项目的最终目标是了解原因和 扩展的(CAG)n三联体重复表达的后果 亨廷顿病基因，并确定这一知识是否可以 将其应用于开发一种治疗该疾病的有效模式。它是 尚不清楚这种三核苷酸重复序列的扩展如何导致 神经元特定子集的过早死亡。此外， 正常IT15基因编码蛋白的功能特性 必须被定义。人类并不构成一个可操控的实验系统 其中可以探索这些问题，目前还没有基因 先天性巨结肠的动物模型。因此，我们计划利用 将外源基因导入小鼠的研究进展 创造一批转基因小鼠，使探索成为可能 在三个关键问题中，(CAG)n突变的不稳定性 小鼠，正常HD等位基因的功能通过表型为空 突变，以及由扩展的(CAG)n重复产生的表型 在引入的人类基因中或适当地定位在内源 老鼠基因。表达人类HD结构的小鼠和改变后的小鼠 将培育出同源基因，建立遗传性先天性心脏病动物模型 将受到详细的分析。 这个项目是一个具有挑战性的项目，就像以前的 在连锁作图和随后的HD基因克隆方面的成功，可能 对高清研究的方方面面产生革命性的影响。如果鼠标 模型表达了重要的神经病理，它将允许更多 详细分析了这些细胞的解剖和生化效应。 扩增的(CAG)n IT15三联重复序列及其表达的遗传学 它与神经元死亡的兴奋性毒素假说的关系，而 提供了一个准确的系统，其中治疗方法可以 测试过。然而，即使表达HD基因的小鼠不能表达任何 异常情况下，它们将值得继续研究，以确定基础 他们对HD缺乏易感性，这可能提供了一条线索 人类的潜在治疗方法。

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.