STRUCTURE AND FUNCTION OF ALZHEIMERS DISEASE PROTEINS

早发性家族性黑色素瘤相关基因的研究进展 阿尔茨海默病（FAD）开辟了新的和令人兴奋的研究途径 这是一种毁灭性的无法治愈的痴呆症的发病机制。 第一个被确定的基因S182可能是导致许多人死亡的原因。 14号染色体相关的FAD病例。 随后的报告指出， 与1号染色体相关FAD相关的同源基因STM 2是 也许最值得注意的是，这两个基因已经开始 定义了一个新的基因家族，该家族在疾病发病机制中很重要 老年痴呆症 这个家族还有两个成员 已经在秀丽隐杆线虫中鉴定出来。 的氨基酸 这四种蛋白质的序列和推定的结构密切相关， 相关，并表明它们可能具有功能相似性。 在这个提议中，我们概述了一系列实验和假设， 将开始批判性地分析这些蛋白质的功能。 在 具体目标1，我们提出了一系列异构体的生产-和 针对S182和STM 2的结构域特异性抗体。 这些抗体被 旨在使其能够用于解决几个具体的假设， 后续具体目标。 我们提出了一些初步的结果， 研究表明成功生产的抗体， S182。 在具体目标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 最后的具体目标，我们将研究可能的功能 S182与STM 2的关系以及C.线虫蛋白SPE-4。 这些 实验将试图从表型上挽救功能丧失的SPE-4 通过引入人S182和STM 2序列的突变体。 除了这些研究活动外， 作为培训和职业发展总体计划的一部分。 活动 在五年的时间里，将为校长提供 作为一名研究人员，有独特的发展机会 科学家，并帮助确保他在学术神经学的成功。

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.