STRUCTURE AND FUNCTION OF ALZHEIMERS DISEASE PROTEINS

早发性家族性白血病相关基因的研究进展 阿尔茨海默病(FAD)开辟了新的令人兴奋的研究途径 研究这种毁灭性的、无法治愈的痴呆症的发病机制。 第一个被发现的基因，S182，可能与许多 14号染色体相关的FAD病例。后续报告标识 与1号染色体相关的FAD相关的同源基因STM2是 也许最值得注意的是这两个基因已经开始 定义一个新的基因家族，该家族在糖尿病的发病机制中起重要作用 阿尔茨海默氏症。这个家族还有另外两个已知的成员 已在秀丽隐杆线虫中鉴定出。氨基酸 这四种蛋白质的序列和推测的结构是紧密的 并表明它们在功能上可能有相似之处。 在这个提案中，我们概述了一系列实验和假设，这些实验和假设 将开始批判性地分析这些蛋白质的功能。在……里面 具体目标1，我们建议生产一系列异构体-和 抗S182和STM2的区域特异性抗体。这些抗体正在被 旨在允许使用它们来解决以下几个特定假设 随后的具体目标。我们给出了一些初步的结果 证明成功地产生了针对人的抗体的研究 S182。在特定的目标2和3中，我们将利用这些抗体来追求 关于这些蛋白质的分布和结构的问题。在……里面 最终的具体目标，我们将调查可能的功能 S182和STM2与线虫蛋白SPE-4的关系这些 实验将尝试挽救spe-4功能丧失的表型 通过引入人类S182和STM2序列获得突变体。 除了这些研究活动外，这项提案正在提交 作为培训和职业发展总体计划的一部分。活动 在五年内概述，这将为校长提供 拥有作为研究发展的独特机会的调查员 科学家，并帮助确保他在学术神经学上的成功。

The recent identification of genes associated with early -onset familial Alzheimer's disease (FAD) opens new and exciting avenues of investigation into the pathogenesis of this devastating and incurable cause of dementia. The first gene to be identified, S182, may be responsible for many of the chromosome 14 associated cases of FAD. Subsequent reports identifying a homologous gene, STM2, implicated in chromosome 1 associated FAD are perhaps most remarkable for the fact that these two genes have begun to define a new gene family which is important in the pathogenesis of Alzheimer's disease. There are two other known members of this family which have been identified in Caenorhabditis elegans. The amino acid sequences and the putative structure of the four proteins are closely related and suggest that they may share functional similarities. In this proposal, we outline a series of experiments and hypotheses which will begin to critically analyze the function of these proteins. In Specific Aim 1, we propose the production of a series of isoform- and domain-specific antibodies to S182 and STM2. These antibodies are being designed to allow their use in addressing several specific hypotheses in subsequent Specific Aims. We present the results of some Preliminary Studies which demonstrate the successful production of the antibody to S182. In Specific Aims 2 and 3, we will exploit these antibodies to pursue questions regarding the distribution and structure of these proteins. In the final Specific Aim, we will investigate the possible functional relationship between S182 and STM2 and the C. elegans protein SPE-4. These experiments will attempt to phenotypically rescue loss of function spe-4 mutants through the introduction of human S182 and STM2 sequences. In addition to these research activities, this proposal is being submitted as part of an overall plan of training and career development. Activities are outlined over a five year period which will provide the Principal Investigator with a unique opportunity to development as a research scientist and help to insure his success in academic neurology.