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.
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