MODEL OF HUMAN MOTOR NEURON DISEASE

突变的小鼠运动神经元变性(MND)表现为成人型 上下层运动神经元进行性变性，导致 瘫痪和过早死亡。它显示出许多人类运动的特征 神经元病(尤指肌萎缩侧索硬化症)研究确定的主要目标是 MND突变将首先检查DNA片段和脊髓mRNA大小 以及候选基因的水平，这些候选基因被认为是紧密相连的 MND的染色体定位。分析较大的DNA片段 从该区域，通过连锁基因鉴定，将被研究是否 这是必要的。症状的发病年龄和进展速度如下 由另外一个或多个未连接的基因控制的。来自遗传学的DNA MND/MND与野生型AKR/J的杂交将使用逆转录病毒探针进行分型 建立初始链接，并通过分析确认 特定的连锁多态，以定位这一重要性状。 对时序效应作用机制的进一步研究将 将遗传信息与疾病的比较结合起来 具有不同时间进程的菌株。这种比较将包括 功能上与原代非常接近的基因的表达 突变的影响，以及那些可能 成为一系列事件的一部分，这些事件导致逐渐的神经元 观察到变性。 MND基因及其时序修饰物的研究应适用于 自发性和遗传性人类运动神经元病。在前者中 对病原体或毒素的敏感性增强的可能性，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轨迹信息来测试人类 地图位置未知的家庭，以及(作为本提案的一部分) 来自人类肌萎缩侧索硬化症患者的脊髓mRNA将被检测出一些水平 在这些标志物中，似乎变化最明显的是老鼠 疾病。长期研究以确定这一过程的性质 能够延缓症状的进展应该特别有价值 从临床上看。

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.