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Transgenic C. elegans as Amyloid Disease Model

转基因线虫作为淀粉样蛋白疾病模型

基本信息

批准号：
8240476
负责人：
Christopher D. Link
金额：
$ 29.71万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-01 至 2013-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Although there is compelling evidence that the beta-amyloid peptide (Abeta) is centrally involved in Alzheimer's disease pathology, the mechanisms of Abeta toxicity and its specific targets remain unresolved. This project is a continuation of our studies using the intensely studied nematode worm Caenorhabditis elegans as a model to investigate the basis of (human) Abeta toxicity. We have previously shown that transgenic worms engineered to express human Abeta 1-42, replicate some aspects of Alzheimer's disease pathology. By a combination of molecular and genetic approaches, we have now identified a set of conserved genes that modulate Abeta toxicity in these transgenic worm models. In addition, analysis of transgenic worms expressing single amino acid variants has led to the identification of an Abeta variant that is substantially non-toxic in vivo. The goal of this proposal is to synthesize these findings to establish: 1) the identity of the toxic Abeta species, 2) the cellular pathways that influence the formation of the toxic species, and 3) the specific cellular targets of Abeta. The Specific Aims of this proposal are to: 1) perform an in vivo structure/function analysis of Abeta toxicity by constructing and characterizing transgenic worms expressing variant Abeta peptides. These studies will directly test the "toxic Abeta oligomer" model, 2) determine the molecular mechanisms by which evolutionarily conserved modifier genes alter Abeta toxicity, and 3) validate the proposed mechanisms for both Abeta toxicity and the protective genes we have identified using mammalian cell culture and primary neuronal cultures. Our proposed studies have direct relevance for the diagnosis and treatment of Alzheimer's disease. The identity of the key toxic form(s) of Abeta may be critical for designing drugs that prevent its formation or toxic activity. Characterization of genes that affect the toxicity of Abeta may be important for both risk assessment and the development of effective interventions for Alzheimer's and other neurodegenerative diseases.

描述（由申请人提供）：尽管有令人信服的证据表明β-淀粉样肽（Abeta）在阿尔茨海默病病理学中起中心作用，但Abeta毒性机制及其特异性靶点仍未得到解决。本项目是我们研究的延续，使用深入研究的线虫秀丽隐杆线虫作为模型，以研究（人类）Abeta毒性的基础。我们以前已经表明，转基因蠕虫工程表达人类Abeta 1-42，复制阿尔茨海默病病理的某些方面。通过分子和遗传学方法的结合，我们现在已经确定了一组保守的基因，调节这些转基因蠕虫模型中的Abeta毒性。此外，对表达单个氨基酸变体的转基因蠕虫的分析已经导致鉴定出在体内基本上无毒的Abeta变体。本提案的目标是综合这些发现，以确定：1）毒性Abeta物质的身份，2）影响毒性物质形成的细胞途径，以及3）Abeta的特定细胞靶点。本提案的具体目的是：1）通过构建和表征表达变体Abeta肽的转基因蠕虫，进行Abeta毒性的体内结构/功能分析。这些研究将直接测试“毒性Abeta寡聚体”模型，2）确定进化上保守的修饰基因改变Abeta毒性的分子机制，和3）验证我们已经使用哺乳动物细胞培养物和原代神经元培养物鉴定的Abeta毒性和保护基因的拟议机制。我们提出的研究对阿尔茨海默病的诊断和治疗有直接的相关性。 Abeta的关键毒性形式的身份可能对于设计防止其形成或毒性活性的药物至关重要。表征影响Abeta毒性的基因可能对风险评估和开发阿尔茨海默病和其他神经退行性疾病的有效干预措施都很重要。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Utility of an improved model of amyloid-beta (Aβ₁₋₄₂) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease.

DOI：
10.1186/1750-1326-7-57
发表时间：
2012-11-21
期刊：
Molecular neurodegeneration
影响因子：
15.1
作者：
McColl G;Roberts BR;Pukala TL;Kenche VB;Roberts CM;Link CD;Ryan TM;Masters CL;Barnham KJ;Bush AI;Cherny RA
通讯作者：
Cherny RA

In vivo aggregation of beta-amyloid peptide variants.

β-淀粉样肽变体的体内聚集。