Transgenic C.elegans as Amyloid Disease Model

描述（由申请人提供）：我们已经设计了一种转基因秀丽隐杆线虫模型系统，其允许人β淀粉样肽（A β 1 -42）在神经元或肌肉组织中的诱导表达。在这两种情况下，Abeta在细胞内积累，形成淀粉样蛋白，并导致细胞病理学。这项工作的目标是了解这种毒性的分子和细胞基础，并研究这些过程如何参与阿尔茨海默病的病理学。建议的项目利用C. elegans，其中许多在其他模型系统中不可用。具体来说，我们将使用正向遗传筛选来鉴定抑制Abeta毒性的突变，从而鉴定参与转导或对抗这种毒性的基因和基因产物。转基因动物也将用于基于微阵列的基因表达研究，从而可以对Abeta毒性的初始细胞反应进行分子描述。将通过构建表达天然和工程化变体Abeta肽的额外转基因系来研究Abeta聚集和毒性之间的关系。将使用基于双链RNA抑制（RNAi）和绿色荧光蛋白（GFP）的转基因报告构建体研究特定基因和基因产物在Abeta毒性中的作用。

DESCRIPTION (provided by applicant): We have engineered a transgenic Caenorhabditis elegans model system that allows inducible expression of human beta amyloid peptide (Abeta1-42) in neuronal or muscle tissue. In both instances, Abeta accumulates intracellularly, forms amyloid, and results in cellular pathology. The goal of the proposed work is to understand the molecular and cellular basis of this toxicity, and to investigate how these processes might be involved in Alzheimer's disease pathology. The proposed project takes advantage of the experimental tools available in C. elegans, many of which are not available in other model systems. Specifically, we will use forward genetic screens to identify mutations that suppress Abeta toxicity, thereby identifying genes and gene products involved in transducing or combating this toxicity. The transgenic animals will also be used in microarray-based gene expression studies, allowing a molecular description of the initial cellular response to Abeta toxicity. The relationship between Abeta aggregation and toxicity will be investigated by the construction of additional transgenic lines expressing natural and engineered variant Abeta peptides. The role of specific genes and gene products in Abeta toxicity will be investigated using double-stranded RNA inhibition (RNAi) and Green Fluorescent Protein (GFP)-based transgenic reporter constructs.