Etiologic studies on EMND: An animal model for ALS

EMND 的病因学研究：ALS 动物模型

• 批准号: 6610626
• 负责人: HUSSNI O MOHAMMED
• 金额: $ 18.8万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610626
• 关键词: amyotrophic lateral sclerosis; antioxidants; blood brain barrier; confocal scanning microscopy; degenerative motor system disease; disease /disorder etiology; high performance liquid chromatography; histochemistry /cytochemistry; laboratory mouse; laboratory rat; membrane permeability; neurotoxins; oxidative stress; pathologic process; tocopherols; vitamin E deficiency

DESCRIPTION (provided by applicant): Equine motor neuron disease (EMND) is a neurodegenerative disorder of the horse characterized by progressive weakness, fasciculations, muscle wasting, and weight loss. Histopathological findings in the brain stem and spinal cord studies reveal that the weakness and muscle wasting result from degeneration of motor neurons in these tissues. The nature and the distribution of the neurodegenerative changes in EMND are strikingly similar to those reported in human progressive muscular atrophy, a form of amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease. As in ALS, the cause(s) of this disease is not known. The long-term objective of our research is to understand the pathogenesis of this disease so that effective control measures can be recommended to prevent its occurrence. We believe that findings on this equine disorder can help to uncover the causative factor(s) for sporadic ALS. Our epidemiologic studies to date have implicated oxidative stress in the risk of EMND and have suggested that some intrinsic factors, e.g. disruption of the blood-brain-barrier, may influence the risk. We hypothesize that the blood-brain barrier (BBB), normally innocuous, can be disrupted as a result of the oxidative stress, exposing the central nervous system to exogenous, highly detrimental substances (i.e. neurotoxic). The proposed studies are aimed to test this hypothesis. We are planning to carry out two randomized trials to evaluate this hypothesis in rats. In the first trial two groups of rats will be identified and allocated randomly to either treatment or control group. The treatment group will receive a diet deficient in vitamin E and the control will receive a normal diet. The two groups will be followed up for a period of time and the permeability of the BBB will be assessed and compared in the two groups. In the second trial the impact of neurotoxic drugs on the risk of neurologic disorder in rats fed diet deficient in antioxidants will be assessed. The treatment group will receive ivermectin and the control group will not. The risk of neurologic disorder will then be assessed in the two groups. In the third hypothesis we will investigate whether the permeability of the BBB is disrupted in horses afflicted with EMND. Data obtained from these pilot studies will represent a major breakthrough towards the understanding of the mechanism of the motor neuron disease and lay the foundation for more thorough investigation.

描述（由申请人提供）：马运动神经元疾病（EMND）是一种马的神经退行性疾病，其特征是进行性无力，束缚，肌肉浪费和体重减轻。脑干和脊髓研究中的组织病理学发现表明，这些组织中运动神经元的变性引起的无力和肌肉浪费。 EMND中神经退行性变化的性质和分布与人类进行性肌肉萎缩中报道的一种非常相似，肌萎缩性侧面硬化症（ALS）或Lou Gehrig病的一种形式。与ALS一样，该疾病的原因尚不清楚。我们研究的长期目标是了解该疾病的发病机理，以便建议采取有效的控制措施以防止其发生。我们认为，关于这种马疾病的发现可以帮助揭示零星ALS的病因。迄今为止，我们的流行病学研究已涉及EMND风险的氧化应激，并提出某些内在因素，例如血脑屏障的破坏可能会影响风险。我们假设血脑屏障（BBB）通常是无害的，可能会因氧化应激而受到破坏，从而将中枢神经系统暴露于外源性，高度有害的物质（即神经毒性）。拟议的研究旨在检验这一假设。我们计划进行两项随机试验，以评估大鼠的这一假设。在第一次试验中，将确定两组大鼠，并随机分配给治疗或对照组。该治疗组将获得缺乏维生素E的饮食，并且对照组将接受正常饮食。这两组将在一段时间内进行跟踪，并将在两组中评估和比较BBB的渗透性。在第二次试验中，将评估神经毒性药物对喂养缺乏抗氧化剂饮食的大鼠神经系统疾病风险的影响。该治疗组将接受依维菌素，对照组将无法接受。然后将在两组中评估神经系统疾病的风险。在第三个假设中，我们将研究BBB的渗透性是否在患有EMND的马中被破坏。从这些初步研究获得的数据将代表理解运动神经元疾病机理的重大突破，并为更彻底的研究奠定了基础。