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: 8501929
• 负责人: Shu-Bing Qian
• 金额: $ 31.22万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501929
• 关键词: Aging; Aging-Related Process; Animals; Behavior monitoring; Biological; Biology; Biology of Aging; Cardiovascular Diseases; Cells; Complement; Complex; Development; Disease; Equilibrium; Event; Gene Expression Profile; Genetic Translation; Goals; Growth; Homeostasis; Insulin; Insulin-Like Growth Factor I; Knowledge; Lead; 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; Staging; Stream; System; Techniques; Testing; Therapeutic; Translation Initiation; Translational Regulation; Translations; Ubiquitin; age related; biological adaptation to stress; cell growth; combat; design; genome-wide; innovation; mTOR protein; multicatalytic endopeptidase complex; novel strategies; novel therapeutics; polypeptide; prevent; programs; protein misfolding; public health relevance; response; sensor; tandem mass spectrometry; tool

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研究，旨在确定预防衰老和年龄相关疾病的潜在分子机制和潜在方法。有人提出，哺乳动物靶标雷帕霉素复合物 1 (mTORC1) 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尚未解决的问题。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发挥着至关重要的作用，但营养信号传导和蛋白质稳态之间的机制联系却知之甚少。此外，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。该项目的目标是在翻译水平上建立营养信号传导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。该提议的基本原理源于营养信号不仅控制蛋白质的初步结果 数量，但也对翻译产品的质量产生负面影响。使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替代翻译。这些发现得出了一个中心假设：营养信号传导与蛋白质稳态协调控制衰老过程。提出以下具体目标来检验这一假设：1）通过关注不同 mTORC1 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）将成为研究响应营养信号和衰老的全基因组翻译重编程的优秀工具。该提案将创新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。对与衰老相关的蛋白质组变化的全面了解将最终导致对抗衰老和与年龄相关的病理的新治疗策略。