2Rs (Refining & reducing) of Animal Models of Multiple Sclerosis

多发性硬化症（MS）是一种脑和脊髓的自身免疫性疾病，导致神经损伤和残疾的积累。虽然在复发性疾病的治疗方面取得了一些进展，但没有控制进行性残疾积累的治疗方法。我们的目标是为这方面的疾病找到有效的治疗方法。MS的主要动物模型，用于在人体试验之前评估药物的作用，是一种被称为实验性自身免疫性脑脊髓炎（EAE）的诱导性麻痹疾病。尽管我们还没有完全？替换？动物用于鉴定治疗疾病的药物我们可以使这些模型更好，使得它们仍然可以检测阻止白色血细胞的破坏性行为的药物，所述破坏性行为驱动神经损伤，同时限制动物的痛苦。这可以通过控制疾病的严重程度和检测药物作用所需的程序时间来实现。连接眼睛和大脑的视神经通常在MS中受损，视觉通路已被选为测试MS新药的重要系统。小鼠不使用视觉作为主要感觉，并容忍视力丧失。我们计划开发一种小鼠系统来模拟这种视神经损伤，使用基因工程小鼠，其白色血细胞被编程为只攻击视神经，而不影响神经系统的其他部分。因此，瘫痪不再发展，从而限制了动物的痛苦。此外，由于进一步的基因工程，通过眼睛用特殊类型的显微镜观察后，眼睛后部视网膜中的细胞将发光。由于视神经受损，它们的发光，细胞体丢失，因此可以很容易地在活体动物中监测神经的存活和死亡。这对现有模型产生了显着的改进，在现有模型中，神经内容的检测是耗时的，并且需要在每个观察点挑选测试动物。由于这种新模型可以连续监测，因此在实验中需要使用的动物更少。此外，我们可以监测视神经的神经冲动传递，以便我们可以首次连续检测损伤和修复。这提供了许多优于现有模型的优点，因此可能会鼓励其他人用本项目中开发的较温和的系统取代现有的严重模型。

Multiple sclerosis (MS) is an autoimmune disease of the brain and spinal cord that results in nerve-damage and the accumulation of disability. Whilst some progress has been made in the treatment of relapsing disease, there are no treatments that control accumulation of progressive-disability. We aim to find useful treatments for this aspect of disease. The main animal-model of MS, used to assess the action of drugs prior to trials in humans, is an induced paralytic-disease called experimental autoimmune encephalomyelitis (EAE). Although we are not yet in a position to completely ?replace? animal use for identifying drugs to treat disease we can make these models better such that they can still detect drugs that stop the destructive actions of the white blood cells that drive nerve damage whilst limiting the suffering to the animals. This can be done by controlling the severity of disease and the length of time in procedure required to detect drug-effects. The optic nerve that links the eye to the brain is often damaged in MS and the visual pathway has been selected as an important system for testing new drugs for MS. Mice, do not use sight as a major sense and tolerate loss of vision. We plan to develop a mouse system that models this optic nerve damage, using genetically-engineered mice, whose white blood cells are programmed to attack only the optic nerve, whilst leaving the rest of the nervous system unaffected. Therefore, paralysis no longer develops and thus limits the suffering of animals. Furthermore, cells in the retina at the back of the eye will be made to glow, due to further genetic-engineering, following observation with a special-type of microscope through the eye. As optic nerves are damaged their glowing, cell-bodies are lost, thus the survival and death of nerves can be easily monitored in the living animal. This generates a significant improvement over existing models, where detection of nerve content is time consuming and requires test-animals to be culled at each observation point. As this new model can be serially-monitored, fewer animals will need to be used in experiments. Furthermore we can monitor nerve impulse transmission of the optic nerve, so that we can serially detect damage and repair for the first time. This provides a number of advantages over existing models and thus may encourage others to replace the existing severe model with the milder system to be developed in this project.