Neuronal-glial interaction in the pathogenesis of ALS

ALS 发病机制中的神经元-胶质细胞相互作用

• 批准号: 6761844
• 负责人: JEFFREY L ELLIOTT
• 金额: $ 27.3万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6761844
• 关键词: amyotrophic lateral sclerosis; cell cell interaction; computer data analysis; electron microscopy; enzyme activity; gene expression; genetically modified animals; genotype; glia; green fluorescent proteins; high performance liquid chromatography; immunocytochemistry; in situ hybridization; laboratory mouse; longitudinal animal study; metalloproteins; motor neurons; neurofilament; neurotoxins; pathologic process; polymerase chain reaction; southern blotting; superoxide dismutase; tissue /cell culture; western blottings

DESCRIPTION (Adapted from applicant's abstract): Because it is motor neurons that invariably die in amyotrophic lateral sclerosis (ALS), most attention has focused on these cells as the primary site where pathophysiologic injury is initiated. However, evidence from human autopsy studies and a transgenic mouse model of familial amyotrophic lateral sclerosis, suggests a potential role for glia in the pathogenesis of disease. To address the cell specific origin of mutant (m) Cu/Zn superoxide dismutase (SOD1) induced disease, we have generated lines of transgenic mice using glial or neuronal specific promoters which allow expression of MSOD1 restricted to either neuronal or glial population. These lines do not develop motor weakness, raising the possibility that disease expression requires both neuronal and glial dysfunction induced by mSOD1. To test this hypothesis, we will determine whether crossing glial and neuronal restricted transgenic lines expressing mSOD1 will reconstitute the disease process in mice and lead to motor neuron degeneration. We will also use a spinal cord organotypic slice model of motor neuron degeneration to address specific mechanisms underlying interactions in fALS, we will generate chimeric mice from wild type and conventional mSOD1 mice, as well as derive chimera from conventional mSOD1 mice and either glial or neuronal specific mSOD1 transgenic liens. These experiments will determine whether glial/neuronal dysfunction involves cell-cell autonomous processes and ascertain whether the disease can be rescued by normal functioning glia. Although the exact mechanism of mSOD1 toxicity is still unknown, recent evidence has supported a critical role for zinc and copper ions. Because neurons and glia both express a repertoire of genes related to zinc/copper binding including the metallothioneins (MTs), we predict that both cell types will manifest abnormal MT expression patterns. In addition, we hypothesize that targeted deletion of neuronal or glial MT genes will significantly accelerate mSOD1- induced disease. Overall, these experiments will test the hypothesis that both neuronal and astroglial dysfunction is required for manifestation of disease in a transgenic murine model of fALS. These results will provide critical insights into mechanisms underlying human motor neuron disease and have important implications for future therapeutic interventions.

描述（改编自申请人摘要）：因为它是运动神经元 在肌萎缩侧索硬化症（ALS）中，大多数人都注意到 这些细胞是病理生理损伤的主要部位， 启动。然而，人类尸检研究和转基因小鼠的证据表明， 家族性肌萎缩侧索硬化模型，表明了一个潜在的作用， 神经胶质在疾病发病机制中的作用。为了解决细胞特异性起源， 突变体（m）Cu/Zn超氧化物歧化酶（SOD 1）诱导的疾病，我们已经产生了 使用神经胶质或神经元特异性启动子的转基因小鼠品系， MSOD 1的表达仅限于神经元或神经胶质细胞群。这些 线不发展运动无力，提高了疾病的可能性， 表达需要mSOD 1诱导的神经元和神经胶质功能障碍。到 测试这一假设，我们将确定是否交叉胶质和神经元 表达mSOD 1的限制性转基因系将重建疾病 在小鼠中进行并导致运动神经元变性。我们还将使用 脊髓器官型切片运动神经元变性模型研究 在fALS的相互作用的具体机制，我们将产生嵌合 小鼠来自野生型和常规mSOD 1小鼠，以及来自 常规mSOD 1小鼠和神经胶质或神经元特异性mSOD 1转基因小鼠 留置权这些实验将确定神经胶质/神经元功能障碍是否 涉及细胞-细胞自主过程，并确定疾病是否可以 被正常功能的神经胶质细胞拯救 虽然mSOD 1毒性的确切机制仍然未知，但最近的研究表明， 有证据支持锌和铜离子的关键作用。因为 神经元和神经胶质细胞都表达与锌/铜相关的基因库， 结合，包括金属硫蛋白（MTs），我们预测，这两种细胞类型， 会表现出异常的MT表达模式此外，我们假设， 神经元或神经胶质MT基因的靶向缺失将显著加速 mSOD 1诱导的疾病。 总之，这些实验将检验神经元和 星形胶质细胞功能障碍是转基因动物疾病表现所必需的。 fALS的鼠模型。这些结果将提供关键的见解， 人类运动神经元疾病的潜在机制， 对未来治疗干预的影响。

项目成果

Assessing the role of immuno-proteasomes in a mouse model of familial ALS.

评估免疫蛋白酶体在家族性 ALS 小鼠模型中的作用。

• DOI: 10.1016/j.expneurol.2007.03.024
• 发表时间: 2007
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Puttaparthi,Krishna;VanKaer,Luc;Elliott,JeffreyL
• 通讯作者: Elliott,JeffreyL

Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins.

家族性肌萎缩侧索硬化症转基因模型中的疾病进展依赖于神经元和非神经元锌结合蛋白。

• DOI: 10.1523/jneurosci.22-20-08790.2002
• 发表时间: 2002
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Puttaparthi,Krishna;Gitomer,WilliamL;Krishnan,Uma;Son,Marjatta;Rajendran,Bhagya;Elliott,JeffreyL
• 通讯作者: Elliott,JeffreyL