NEURON CULTURES FOR CLN6 BATTEN DISEASE STUDIES

描述(应用摘要)：神经元蜡样脂褐素增多症(NCLS， 巴顿病)是一种遗传性儿童神经退行性疾病。的目的是 这一应用是利用从绵羊模型发展而来的神经元培养作为 一种人类疾病的体外模型及其与整个动物的结合使用 研究，研究神经退行性变的机制并探索可能的 治疗。 NCLS的特点是严重的神经变性和细胞内 线粒体三磷酸腺苷合成酶c亚基的积累。皮质神经元 已从受影响的绵羊和储藏体中建立了培养体系 在培养细胞中观察到的蓄积。这项调查将优化这些 神经元培养作为原位病理模型。它的作用机制 将在他们身上研究神经退行性变。需要测试的具体假设包括 C亚单位的储存与神经退行性变直接相关，即a 内酶体-溶酶体途径的破坏是神经退变的中心 而亚基C的积累导致低聚物的过度活性 神经细胞质膜中的C亚单位。细胞凋亡和细胞凋亡的作用 将检测兴奋毒性以及IGF1和其他生长因子的疗效 测试了可能克服神经退行性变的因素。嵌合正常/受影响 将产生绵羊来描述基因和酶的可能性 心理治疗。将监测受影响绵羊的临床病程。 转基因IGF1在大脑中过表达，以确定这是否改善 症状的发展。可能的治疗方法将在整个动物身上进行测试 实验。 这些结果将与理解NCLS的病理生物学相关，并将 测试可能的治疗方法带来益处的可能性。调查结果也将是 与了解其他储存神经退行性疾病的蛋白质有关， 比如阿尔茨海默氏症。

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.