Linking Nutrient Signaling and Protein Homeostasis in Mammalian Aging

将哺乳动物衰老过程中的营养信号传导与蛋白质稳态联系起来

• 批准号: 9288108
• 负责人: Shu-Bing Qian
• 金额: $ 31.78万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288108
• 关键词: Aging; Aging-Related Process; Animals; Behavior monitoring; Biological; Biology; Biology of Aging; Cardiovascular Diseases; Cells; Complement; Complex; Controlled Study; Development; Disease; Equilibrium; Event; FRAP1 gene; Genetic Translation; Goals; Growth; Hyperactive behavior; Insulin; Insulin-Like Growth Factor I; Knowledge; Lead; Life Extension; Link; Longevity; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Metabolic Diseases; Metabolism; Methods; Molecular; Molecular Chaperones; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organism; Pathology; Pathway interactions; Plant Roots; Positioning Attribute; Process; Protein Biosynthesis; Protein Conformation; Protein-Serine-Threonine Kinases; Proteins; Proteome; Public Health; Regulation; Reporting; Research; Resolution; Ribosomes; Risk Factors; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Sirolimus; System; Techniques; Testing; Therapeutic; Translation Initiation; Translational Regulation; Translations; Ubiquitin; Vitronectin; age related; biological adaptation to stress; cell growth; combat; design; genome-wide; innovation; misfolded protein; multicatalytic endopeptidase complex; novel strategies; novel therapeutic intervention; polypeptide; prevent; proteostasis; public health relevance; response; ribosome profiling; sensor; tandem mass spectrometry; tool; transcriptome

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.

描述（由申请人提供）：雷帕霉素延长多种生物体寿命的发现引发了一系列旨在确定潜在分子机制和预防衰老和年龄相关疾病的潜在方法的研究。研究表明，哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）通过调节mRNA翻译来控制生长和衰老。然而，蛋白质合成的减少如何延长寿命仍然是一个悬而未决的问题。蛋白质稳态是指细胞蛋白质的合成、成熟和降解之间的适当平衡。尽管蛋白质稳态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稳态之间的机制联系却知之甚少。此外，人们对衰老相关的蛋白质组变化知之甚少，这在很大程度上是由于技术限制。本项目的目标是在翻译水平上建立营养信号和蛋白质稳态之间的功能联系，并确定与衰老相关的替代翻译。这一建议的基本原理来自于初步的结果，即营养信号不仅控制蛋白质， 数量，但也负调控翻译产物的质量。利用高分辨率核糖体分析技术，我们发现了一种由营养信号控制的普遍的替代翻译。这些发现导致了核心假设，即营养信号与蛋白质稳态协调控制衰老过程。提出了以下具体目标来检验这一假设：1）通过关注不同mTORC 1下游靶标的翻译方面，剖析营养信号传导和蛋白质稳态之间的分子联系。2)定义营养信号在新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)确定哺乳动物衰老中的翻译重编程，特别是营养信号控制的选择性翻译和替代翻译起始。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极好工具。该建议将创新的方法整合到翻译控制的基础研究中。成功完成拟议的研究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年龄相关病理的新治疗策略。

项目成果

TISdb: a database for alternative translation initiation in mammalian cells.

• DOI: 10.1093/nar/gkt1085
• 发表时间: 2014-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Wan J;Qian SB
• 通讯作者: Qian SB

Translational control of the cytosolic stress response by mitochondrial ribosomal protein L18.

• DOI: 10.1038/nsmb.3010
• 发表时间: 2015-05
• 期刊: NATURE STRUCTURAL & MOLECULAR BIOLOGY
• 影响因子: 16.8
• 作者: Zhang, Xingqian;Gao, Xiangwei;Coots, Ryan Alex;Conn, Crystal S.;Liu, Botao;Qian, Shu-Bing
• 通讯作者: Qian, Shu-Bing

Translational reprogramming in cellular stress response.

• DOI: 10.1002/wrna.1212
• 发表时间: 2014-05
• 期刊: WILEY INTERDISCIPLINARY REVIEWS-RNA
• 影响因子: 7.3
• 作者: Liu, Botao;Qian, Shu-Bing
• 通讯作者: Qian, Shu-Bing