Linking Nutrient Signaling and Protein Homeostasis in Mammalian Aging

描述(申请人提供)：雷帕霉素可以延长不同生物的寿命，这一发现引发了一系列研究，旨在确定潜在的分子机制和潜在的预防衰老和与年龄相关的疾病的方法。已有研究表明，哺乳动物靶标雷帕霉素复合体1(MTORC1)通过调节mRNA的翻译来控制生长和衰老。然而，蛋白质合成减少如何延长寿命仍然是一个悬而未决的问题。蛋白质动态平衡是指细胞蛋白质的合成、成熟和降解之间的适当平衡。尽管蛋白质动态平衡在生长和衰老中起着至关重要的作用，但营养信号和蛋白质动态平衡之间的机制联系却鲜为人知。此外，在很大程度上由于技术限制，人们对与衰老相关的蛋白质组变化知之甚少。这个项目的目标是在翻译水平上建立营养信号和蛋白质动态平衡之间的功能联系，并确定与衰老相关的替代翻译。这一建议的理论基础来自于初步结果，即营养信号不仅控制蛋白质 这不仅限制了翻译产品的数量，而且对翻译产品的质量也产生了负面影响。利用高分辨率核糖体图谱技术，我们发现了一种由营养信号控制的流行的替代翻译。这些发现导致了一个中心假设，即在控制衰老过程中，营养信号与蛋白质稳态相协调。为了验证这一假说，提出了以下具体目标：1)通过关注不同mTORC1下游靶标的翻译方面，剖析营养信号和蛋白质动态平衡之间的分子联系。2)确定营养信号在初生链的共翻译事件中的作用，包括共翻译折叠、降解和伴侣相互作用。3)确定哺乳动物衰老过程中的翻译重编程，特别是营养信号控制的选择性翻译和选择性翻译起始。我们新开发的全球 翻译起始测序技术(GTI-Seq)将成为研究全基因组翻译重编程响应营养信号和衰老的一个很好的工具。这一建议将创新的方法整合到翻译控制的基础研究中。这项拟议研究的成功完成将改变我们对衰老生物学的认识。对衰老相关蛋白质组变化的全面了解将最终导致对抗衰老和衰老相关病理的新的治疗策略。

DESCRIPTION (provided by applicant): The discovery that rapamycin extends the life span of diverse organisms has triggered a flurry of studies aimed at identifying the underlying molecular mechanisms and potential ways to prevent aging and age-related diseases. It has been suggested that the mammalian target of rapamycin complex 1 (mTORC1) controls growth and aging by regulating mRNA translation. However, how a decrease in protein synthesis can extend lifespan remains an unresolved issue. Protein homeostasis refers to a proper balance between synthesis, maturation, and degradation of cellular proteins. Despite the crucial role of protein homeostasis in growth and aging, the mechanistic connection between nutrient signaling and protein homeostasis is poorly understood. In addition, little is known about aging-associated proteome changes due in large part to technical limitations. The goal of this project is to establish the functional connection between nutrient signaling and protein homeostasis at the level of translation, and to determine aging-associated alternative translation. The rationale for this proposal grew out of the preliminary results that nutrient signaling not only controls protein quantity, but also negatively regulates the quality of translational products. Using high resolutio ribosome profiling technique, we uncovered a prevailing alternative translation controlled by nutrient signaling. These findings led to the central hypothesis that nutrient signaling coordinates with protein homeostasis in controlling the aging process. The following specific aims are proposed to test this hypothesis: 1) Dissect the molecular linkage between nutrient signaling and protein homeostasis by focusing on translational aspects of different mTORC1 down- stream targets. 2) Define the role of nutrient signaling in co-translational events of nascent chains, including co-translational folding, degradation, and chaperone interaction. 3) Determine translational re-programming in mammalian aging, in particular the nutrient signaling-controlled selective translation and alternative translation initiation. Our newly-developed global translation initiation sequencing technique (GTI-Seq) will serve as an excellent tool to investigate the genome-wide translational re-programming in response to nutrient signaling and aging. This proposal integrates innovative approaches into fundamental studies of translational control. Successful completion of the proposed studies will transform our knowledge about the biology of aging. A comprehensive understanding of aging-associated proteome changes will ultimately lead to new therapeutic strategies for combating aging and age-related pathologies.