NEURON CULTURES FOR CLN6 BATTEN DISEASE STUDIES

描述（应用摘要）：神经元蜡样脂褐质沉积症（NCL， Batten病）是遗传性儿科神经退行性疾病。的目的 该应用是利用从绵羊模型开发的神经元培养物， 人疾病的体外模型，并将其与整个动物组合使用 研究，研究神经变性的机制，探索可能的 治疗 NCL的特征在于严重的神经变性和细胞内的神经变性。 线粒体ATP合成酶c亚基的积累。皮质神经元 从患病绵羊和储存体中建立了培养物 在培养的细胞中观察到蓄积。这项调查将优化这些 神经元培养物作为原位病理学的模型。的机理 将在其中研究神经变性。待检验的具体假设为 亚基c的储存与神经退行性变直接相关， 内体-溶酶体途径的中断是神经变性的中心 并且亚基C的积累导致寡聚体的过度活性， 亚单位C离子孔的神经元质膜。细胞凋亡的作用， 将检查兴奋性毒性，并检查IGF 1和其他生长因子的功效。 可能克服神经变性的因素进行了测试。嵌合正常/受累 将产生绵羊来描绘基因和酶的可能性， 疗法将监测患病绵羊的临床病程 转基因过表达IGF 1在大脑中，以确定这是否改善 症状的发展。将在整只动物中测试可能的治疗方法 实验 结果将有助于理解NCL的病理生物学， 测试可能的治疗方法的可能性。调查结果还将 与理解其他蛋白质储存神经退行性疾病相关， 例如阿尔茨海默氏病。

DESCRIPTION (application abstract): The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are inherited pediatric neurodegenerative diseases. The aim of this application is to exploit neuron cultures developed from an ovine model as an in vitro model of human disease and use it, in combination with whole animal studies, to study the mechanism of neurodegeneration and explore possible therapies. The NCLs are characterized by profound neurodegeneration and the intracellular accumulation of subunit c of mitochondrial ATP synthase. Cortical neuronal cultures have been established from affected sheep and storage body accumulation observed in cultured cells. This investigation will optimize these neuron Cultures as a model of the in situ pathology. The mechanism of neurodegeneration will be studied in them. Specific hypotheses to be tested are that subunit c storage is directly related to neurodegeneration, that a disruption in the endosome-lysosome pathway is central to the neurodegeneration and that accumulation of subunit c results in over-activity of an oligomeric subunit c ionpore in the neuronal plasma membrane. The role of apoptosis and excitotoxicity will be examined and the efficacy of IGF1 and other growth factors that might overcome neurodegeneration tested. Chimeric normal/affected sheep will be generated to delineate the possibilities for gene and enzyme therapy. The clinical course of disease will be monitored in affected sheep transgenically overexpressing IGF1 in brain, to determine if this ameliorates the development of symptoms. Possible therapies will be tested in whole animal experiments. Results will be relevant to understanding the pathobiology of the NCLs and will test the likelihood of benefits of possible treatments. Findings will also be relevant to understanding other protein storing neurodegenerative diseases, such as Alzheimer's disease.