MODEL OF HUMAN MOTOR NEURON DISEASE

小鼠突变型运动神经元变性（Mnd）表现出成年发病 上、下运动神经元进行性退化，导致 瘫痪和过早死亡 它表现出许多与人类运动有关的特征 神经元疾病，特别是肌萎缩侧索硬化症。 研究确定的主要目标 Mnd突变将首先检查DNA片段和脊髓mRNA大小 以及已知的候选基因的水平， Mnd的染色体定位。 分析较大的DNA片段 从该地区，确定使用连锁基因，将进行研究，如果 必要 发病年龄和症状进展的速度是 由一个或多个额外的非连锁基因控制。 DNA遗传学 将使用逆转录病毒探针对Mnd/Mnd与野生型AKR/J的杂交进行分型 建立初步联系，并通过分析 特定的连锁多态性，以映射这一重要性状。 对时间效应的作用机制的进一步研究将有助于 联合收割机将遗传信息与 具有不同时间进程的菌株。 这些比较将包括 功能上非常接近原发性肿瘤的基因表达 突变的影响，以及这些基因的表达， 是导致神经元逐渐 观察到退化。 Mnd基因及其时间修饰物的研究应适用于 自发性和遗传性人类运动神经元疾病。在前 对病原体或毒素的易感性增强的可能性，和/或 在大多数情况下，多基因效应似乎是可能的。 其他 研究人员正在利用老鼠的基因位点信息来测试人类 地图位置未知的家庭，以及（作为本提案的一部分） 将测试来自人ALS病例的脊髓mRNA的一些水平， 这些标记在老鼠身上变化最明显 疾病 长期研究，以确定过程的性质， 可以减缓症状的进展应该特别有价值 临床上

The mouse mutant Motor neuron degeneration (Mnd) exhibits an adult-onset progressive degeneration of upper and lower motor neurons, leading to paralysis and premature death. It shows many features with human motor neuron diseases, esp ALS. Studies to identify the primary target of the Mnd mutation will first examine DNA fragments and spinal cord mRNA sizes and levels from candidate genes which are known to map in close proximity to the chromosomal location of Mnd. Analysis of larger pieces of DNA from that region, identified using linked genes, will be studied if necessary. The age of onset and speed of progression of the symptoms are controlled by an additional unlinked gene or genes. DNA from genetics cross of Mnd/Mnd to wild-type AKR/J will be typed using retroviral probes to establish an initial linkage, with confirmation by analysis of specific linked polymorphisms, in order to map this important trait. Further studies of the mechanism of action of the timing effect will combine the genetic information with comparisons of the disease in strains with different time-courses. Such comparisons will include expression of genes which are functionally very close to the primary effects of the mutation, as well as expression of those genes which may be part of the cascade of events which leads to the gradual neuronal degeneration observed. Studies of the Mnd gene plus its timing modifier should be applicable to both spontaneous and hereditary human motor neuron disease. in the former the possibility of enhanced susceptibility to a pathogen or toxin, and/or multigenic effect seem likely in the majority of cases. Other investigators are using the mouse locus information to test human families with unknown map locations, and (as part of this proposal) spinal cord mRNA from human ALS cases will be tested for levels of some of those markers which seem to change most specifically in the mouse disease. Long-range studies to determine the nature of the process which can slow the progression of the symptoms should be especially valuable clinically.