C LEGANS MODEL FOR ALZHEIMERS DISEASE

描述：阿尔茨海默病是一种毁灭性的常见病。 中枢神经系统，对家族形式的研究发现了一种 与疾病发展有牵连的基因座数目。这个 作为本提案主题的线虫模型基于 发现sel-12基因编码的蛋白质与两种蛋白质高度相似 与早发性家族性阿尔茨海默病相关的基因。这个 对预测的线虫和人类蛋白质的显著保护 这表明它们的功能也可能被保存下来。 此外，几乎所有的突变都与早发性家族性 阿尔茨海默病患者体内的氨基酸会发生改变，这些氨基酸在 SEL-12。首席调查员希望将古典音乐的工具 和分子遗传学研究涉及线虫的基本问题 SEL-12及其人类同源物的结构和功能。具体的 这项建议的目的是：一、SEL-12的基本特征。这个 拟议的实验将直接测试S182的功能等价性， STM2和SEL-12。其他实验关注的是建立零 表型，表征表达模式，识别行为 缺陷，产生针对SEL-12的抗体，并鉴定线虫基因 它们与SEL-12高度相似。二、改造SEL-12转基因 [“SEL-12(ALZ)”]含有与早发性家族性 阿尔茨海默氏症。拟议的实验涉及到 转Sel-12(Alz)基因的产生及遗传和表型分析 台词。三、外源基因的鉴定和特征 Sel-12(AR171)和Sel-12(Alz)的抑制子。建议的实验是 与sel-12(Ar171)和sel-12(Alz)突变体的逆转有关，以及 抑制基因的遗传和分子分析。

DESCRIPTION: Alzheimer's disease is a devastating and common disease of the central nervous system, and studies of familial forms have identified a number of loci that are implicated in the development of the disease. The C. elegans model that is the subject of this proposal is based on the finding that the sel-12 gene encodes a protein that is highly similar to two genes associated with early-onset familial Alzheimer's disease. The remarkable conservation of the predicted C. elegans and human proteins suggests that their functions are likely to be conserved as well. Furthermore, nearly all mutations associated with early-onset familial Alzheimer's disease in people alter amino acids that are identical in SEL-12. The Principal Investigator hopes to bring the tools of classical and molecular genetic studies in C. elegans to bear on fundamental issues of the structure and function of SEL-12 and its human homologs. The specific aims of this proposal are: I.A basic characterization of sel-12. The proposed experiments will directly test the functional equivalence of S182, STM2 and SEL-12. Other experiments are concerned with establishing the null phenotype, characterizing the expression pattern, identifying behavioral defects, generating antibodies to SEL-12, and identifying C. elegans genes that are highly similar to sel-12. II. To engineer sel-12 transgenes ["sel-12(Alz)"] containing alterations associated with early-onset familial Alzheimer's disease. The proposed experiments are concerned with the generation and genetic and phenotypic analyses of sel-12(Alz) transgenic lines. III. The identification and characterization of extragenic suppressors of sel-12(ar171) and sel-12(Alz). The proposed experiments are concerned with the reversion of sel-12(ar171) and sel-12(Alz) mutants, and genetic and molecular analyses of suppressor genes.