Comparative Modeling of Neurodegenerative Diseases

神经退行性疾病的比较模型

• 批准号: 6610250
• 负责人: Christopher D. Link
• 金额: $ 28.43万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610250
• 关键词: Caenorhabditis elegans; DNA damage; alpha synuclein; cellular pathology; chemical aggregate; cytotoxicity; double stranded RNA; gene expression; gene mutation; genetic models; genetic transcription; genetically modified animals; immunoprecipitation; mass spectrometry; microarray technology; neural degeneration; pathologic process; polymerase chain reaction; superoxide dismutase; tau proteins

DESCRIPTION (provided by applicant): Numerous age-associated neurodegenerative diseases [e.g., Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), etc.] are associated with aggregation of disease-specific proteins. The finding that the genes encoding these proteins are mutated in some familial forms of these diseases strongly argues that these aggregating proteins cause these diseases. However, for all these diseases the relationship between protein aggregation and cellular pathology has not been clearly established. It is also unknown if the common association of protein aggregation with these diseases reflects a common underlying toxic mechanism, or, alternatively, a common downstream result of cell pathology. We will seek to identify the molecular consequences resulting from the aggregation of three different disease-associated proteins by individually expressing these proteins in a transgenic Caenorhabditis elegans model system. These molecular consequences will be determined by DNA microarray-based gene expression studies and co-immunoprecipitation analyses. Comparison of the molecular responses to expression of different disease-associated proteins will allow identification of common and disease-specific responses. We will then use the molecular genetic tools available in C. elegans to manipulate these molecular responses to determine their role in disease protein toxicity. These studies will directly test whether there is a common underlying toxic mechanism for these neurodegenerative diseases.

描述（由申请人提供）：许多与年龄相关的神经退行性疾病[例如阿尔茨海默病（AD）、帕金森病（PD）、肌萎缩侧索硬化症（ALS）、亨廷顿病（HD）等]与疾病的聚集有关-特定蛋白质。编码这些蛋白质的基因在这些疾病的某些家族形式中发生突变的发现有力地证明了这些聚集蛋白质导致了这些疾病。然而，对于所有这些疾病，蛋白质聚集和细胞病理学之间的关系尚未明确确定。目前还不清楚蛋白质聚集与这些疾病的共同关联是否反映了共同的潜在毒性机制，或者细胞病理学的共同下游结果。我们将通过在转基因秀丽隐杆线虫模型系统中单独表达三种不同疾病相关蛋白的聚集来寻求鉴定这些蛋白的聚集所产生的分子后果。这些分子结果将通过基于 DNA 微阵列的基因表达研究和免疫共沉淀分析来确定。比较不同疾病相关蛋白表达的分子反应将有助于识别常见反应和疾病特异性反应。然后，我们将使用线虫中可用的分子遗传工具来操纵这些分子反应，以确定它们在疾病蛋白质毒性中的作用。这些研究将直接测试这些神经退行性疾病是否存在共同的潜在毒性机制。