BATTEN DISEASE

该项目旨在确定先天性生化异常， 遗传性神经退行性疾病的儿童称为神经元 蜡样脂褐质病（NCL，Batten病）。 这是一个延续， 目前的工作使用绵羊模型和比较研究，与变化 专注于细胞生物学研究，并扩大合作 芬兰的哈尔蒂亚博士专门研究婴儿型 这种形式不同于绵羊和晚期婴儿和青少年 线粒体ATP合酶c亚基 具体来说就是积累。 在羊身上学到的经验和技能 项目及其对人类形态的延伸将适用于 婴儿疾病中储存物质的表征。 从 特别是积累的物种的性质，一个战略将是 以确定潜在的生化损伤。 抗体 将产生用于光和电子免疫细胞化学研究 微观层面。 绵羊的工作将集中在确定亚基c的具体途径 周转，从它的合成，纳入线粒体，并通过 正常的退化。 不同形式的亚基c储存NCL反映了 在这一途径中影响不同相关蛋白质的突变， 而不是单一基因产物的不同突变。 比较研究 不同形式的NCL将有助于确定这一途径。 的 方法将利用新开发的放射性标记的E。杆菌 在细胞培养物中表达亚基c（具有前导序列）， 通过表征指示的 亚细胞区室 针对不同表位的抗体 包括前导序列和成熟的亚基C以及 特定的细胞器将用于免疫细胞化学研究。 潜在缺陷的定义对于更好地 诊断方法，包括产前诊断和杂合子 检测并可能与治疗相关。 考虑到 ATP合成酶复合物，该项目也将有相关性， 了解其组装和拆卸。

This project seeks to define the inborn biochemical anomalies in the inherited neuro-degenerative diseases of children known as the neuronal ceroid-lipofuscinoses (NCL, Batten disease). It is a continuation of present work using the ovine model and comparative studies, with a change of focus to cellular biology investigations and extends collaboration with Dr. Haltia of Finland specifically investigating the infantile form. This form is distinct from the ovine and late infantile and juvenile forms and others where subunit c of mitochondrial ATP synthase specifically accumulates. The experience and skills learned in the ovine project and its extension of human forms will be applied to the characterization of the storage material in the infantile disease. From the Nature of specifically accumulated species, a strategy will be developed to determine the underlying biochemical lesion. Antibodies will be produced for immunocytochemical studies at light and electron microscopic levels. The ovine work will focus on defining the specific pathway of subunit c turnover, from its synthesis, incorporation into mitochondria and through its normal degradation. Different forms of subunit c storage NCL reflect mutations affecting different associated proteins in this pathway rather than different mutations of a single gene product. Comparative studies with different forms of NCL will help define this pathway. The methodologies will exploit the newly developed radiolabelled E. coli expressed subunit c (with lead sequences) in cell culture and reconstitution studies augmented by characterization of indicated subcellular compartments. Antibodies against different epitopes including lead sequences and mature subunit c as well as markers for particular organelles will be used in immunocytochemical studies. Definition of the underlying defect(s) would have significance for better methods of diagnosis, including prenatal diagnosis and heterozygote detection and may have relevance to therapy. Given the significance of ATP synthase complex, the project will also have relevance to understanding of its assembly and disassembly.