AGE-ASSOCIATED NEUROPROTECTION BY INSULIN/IGF-1 SIGNALING: FROM WORM TO MOUSE

胰岛素/IGF-1信号传导的年龄相关神经保护：从蠕虫到小鼠

• 批准号: 7568477
• 负责人: Andrew G Dillin
• 金额: $ 38.68万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568477
• 关键词: Address; Age; Age of Onset; Aging; Aging-Related Process; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid beta-Protein; Animals; Apis; Behavioral; Biochemical; Bioinformatics; Biological; Caenorhabditis elegans; Cells; Collaborations; Communities; Complement; Coupled; Data; Disease; Electron Transport; Elements; Event; Future; Gene Expression Profile; Genetic; Goals; Human; IGF-1 Signaling Pathway; Inflammation; Insulin; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Knowledge; Letters; Life; Link; Location; Long-Term Potentiation; Mammals; Mediating; Methodology; Micelles; Mitochondria; Modeling; Molecular; Molecular Conformation; Molecular Weight; Movement; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathway interactions; Production; Program Research Project Grants; Protein Isoforms; Proteins; Proteomics; Regulation; Regulatory Pathway; Reporting; Research; Research Personnel; Risk Factors; Role; Signal Transduction; Structure; Subfamily lentivirinae; Technology; Testing; Toxic effect; Transcript; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Variant; Vertebrates; Work; base; design; dietary restriction; forkhead protein; gene discovery; gene function; in vitro Assay; in vivo; mouse model; mutant; neuron loss; neuroprotection; novel strategies; presenilin; presenilin-1; prevent; programs; protein aggregation; research study; three dimensional structure

The greatest risk factor for nearly all neurodegenerative diseases is aging, yet, the molecular identity of the age associated mechanisms are not known. The central hypothesis of this proposal is that continual production of aggregation prone proteins eventually leads to age onset proteotoxicity and disease. The key question to address is what are the molecular mechanisms that prevent proteotoxicity during early life that become compromised with age. To address this question, in the first part of our work,we will expand upon our results in C. elegans that point towards a protective disaggregation activity and the formation of larger, less toxic high molecular weight aggregates that are regulated by the insulin/IGF-1 pathway. From our preliminary results it is clear that a distinct biochemical activity encoded by the HSF-1 transcriptome is partially responsible for the protective dissaggregation activity. However, it is not clear if there is a distinct active aggregation activity encoded by the DAF-16 transcriptome to create large, less toxic, A(3structures. Alternatively, the DAF-16 transcriptome may regulate the expression of factors critical for a cellular event, such as endocytic movement of A(3toxic structures that results in large aggregates forming from smaller toxic structures. To identify and characterize the components of these activities, we will employ bioinformatic, genetic and proteomic analysis to complement the biochemical approaches of the Kelly lab and the cell biological analysis of the Balch lab.In the next part of our work, in collaboration with the Masliah lab, we will evaluate whether the same protective mechanisms exists in mammals. In the third specific aim, using biophysical data generated in the Riek lab, we will create transgenic worms that express structurally trapped isoforms of A(31-42. Genetic modifiers of proteotoxicityfrom the worm-based models will be further explored in murine models by the Masliah lab using lentivirus technology. Finally, our preliminary results indicate that insulin/IGF-1 signaling is not the only aging regulatory pathway that can protect animals from Apl-42 mediated toxicity. We will broaden the scope of our research to understand how reduced mitochondrial function and diet restriction can delay age onset proteotoxicity and their potential mechanism.

几乎所有神经退行性疾病的最大危险因素是衰老，然而，神经退行性疾病的分子特征 年龄相关机制尚不清楚。该提案的中心假设是持续 易于聚集的蛋白质的产生最终导致衰老性蛋白质毒性和疾病。关键 要解决的问题是，在生命早期防止蛋白质毒性的分子机制是什么？ 随着年龄的增长而妥协。为了解决这个问题，在我们工作的第一部分，我们将扩展 我们对秀丽隐杆线虫的研究结果表明，存在保护性解聚活性并形成更大的、 毒性较小的高分子量聚集体，受胰岛素/IGF-1 途径调节。来自我们的 初步结果表明，HSF-1 转录组编码的独特生化活性是 部分负责保护性分解活动。但尚不清楚是否存在明显的 DAF-16 转录组编码的主动聚集活性可产生较大的、毒性较小的 A(3 结构。 或者，DAF-16 转录组可以调节对细胞事件至关重要的因子的表达， 例如 A(3 毒性结构的内吞运动，导致较小的聚集体形成大的聚集体 有毒结构。为了识别和描述这些活动的组成部分，我们将采用 生物信息、遗传和蛋白质组分析，以补充凯利实验室的生化方法 以及 Balch 实验室的细胞生物学分析。在我们工作的下一部分中，与 Masliah 合作 在实验室中，我们将评估哺乳动物中是否存在相同的保护机制。在第三个具体目标中， 利用 Riek 实验室生成的生物物理数据，我们将创建表达结构的转基因蠕虫 A(31-42) 的捕获亚型。来自基于蠕虫的模型的蛋白毒性的遗传修饰剂将进一步 Masliah 实验室利用慢病毒技术在小鼠模型中进行了探索。最后，我们的初步结果 表明胰岛素/IGF-1信号传导并不是唯一可以保护动物免受衰老影响的途径 Apl-42 介导的毒性。我们将扩大我们的研究范围，以了解如何减少 线粒体功能和饮食限制可以延缓年龄发生的蛋白质毒性及其潜在机制。