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

几乎所有神经退行性疾病的最大风险因素是衰老，然而， 与年龄相关的机制尚不清楚。这一建议的核心假设是， 易于聚集的蛋白质的产生最终导致衰老性蛋白毒性和疾病。关键 要解决的问题是，在生命早期防止蛋白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，我们将扩大 我们在C.这表明了一种保护性的解聚活性和形成更大的， 毒性较小的高分子量聚集体，其由胰岛素/IGF-1途径调节。从我们 初步结果清楚的是，由HSF-1转录组编码的独特的生物化学活性， 部分负责保护性解聚活性。然而，目前尚不清楚是否存在明显的 活性聚集活性由α-16转录组编码，以产生大的、毒性较小的A（3结构。 或者，β-16转录组可以调节细胞事件关键因子的表达， 如A β毒性结构的内吞运动，导致从较小的聚集体形成较大的聚集体， 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 生物信息学，遗传学和蛋白质组学分析，以补充凯利实验室的生化方法 和Balch实验室的细胞生物学分析。在我们工作的下一部分，与Masliah合作， 实验室，我们将评估是否同样的保护机制存在于哺乳动物。在第三个具体目标中， 利用Riek实验室产生的生物物理数据，我们将创造出转基因蠕虫， 被捕获的同种型A（31-42.基于蠕虫模型的蛋白质毒性遗传修饰剂将进一步 Masliah实验室使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 这表明胰岛素/IGF-1信号传导并不是唯一可以保护动物免受衰老的调节途径。 APL-42介导的毒性。我们将扩大研究范围， 线粒体功能和饮食限制可延缓衰老蛋白毒性及其可能机制。

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.