Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS).
Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS).
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DOI：
10.1371/journal.pone.0023244
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Shaw PJ
中科院分区：
文献类型：
--
作者：
Mead RJ;Bennett EJ;Kennerley AJ;Sharp P;Sunyach C;Kasher P;Berwick J;Pettmann B;Battaglia G;Azzouz M;Grierson A;Shaw PJ
人SOD 1G 93 A转基因小鼠自1994年开发以来已被广泛用作肌萎缩侧索硬化症（ALS）的模型。在这段时间里，突变SOD 1的毒性已经获得了大量的见解使用这个和其他突变SOD转基因小鼠模型。它们都表现出对运动神经元的选择性毒性，并且在某些情况下表现出在人类疾病中观察到的病理学特征。这些模型有两个主要缺点。首先，在这些模型中生成稳健的临床前数据已被强调为一个值得关注的领域。其次，在这些模型中进行单个临床前实验所需的时间（3-4个月）是开发新疗法的障碍。我们已经从原始的混合背景（SJLxC 57 BL/6）SOD 1G 93 A转基因系开发了近交C57 BL/6小鼠系，并且在此显示疾病过程是显著一致的并且更不易于背景噪声，使得能够减少用于测试治疗剂的小鼠数量。其次，我们已经确定了非常早期的读数，显示与正常小鼠相比，运动功能大幅下降。这种运动功能的丧失使我们能够为在该模型中观察到的肌纤维去神经支配的初始阶段开发早期、灵敏和快速的筛选方案。我们描述了多个，定量读出的运动功能，可用于询问这种早期机制。这种方法将增加生产量，降低成本，同时降低所涉及的实验程序的严格性。
The human SOD1G93A transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS). In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3–4 months) is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6) SOD1G93A transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.
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影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
DOI：
10.1016/j.molbrainres.2004.07.002
发表时间：
2004-11-04
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Alexander, GM;Erwin, KL;Heiman-Patterson, TD
通讯作者：
Heiman-Patterson, TD
影响因子：
3.7
作者：
Dupuis L;Gonzalez de Aguilar JL;Echaniz-Laguna A;Eschbach J;Rene F;Oudart H;Halter B;Huze C;Schaeffer L;Bouillaud F;Loeffler JP
通讯作者：
Loeffler JP
影响因子：
4.4
作者：
Bendotti, C;Calvaresi, N;De Biasi, S
通讯作者：
De Biasi, S
影响因子：
1.7
作者：
Barneoud, P;Lolivier, J;Moser, P
通讯作者：
Moser, P