Role of dS6 phosphorylation in dTORC1/dS6K mediated longevity in Drosophila

dS6 磷酸化在 dTORC1/dS6K 介导的果蝇寿命中的作用

基本信息

批准号：
8249374
负责人：
GEORGE THOMAS
金额：
$ 21.59万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249374
关键词：
Accounting Adipose tissue Affect Aging American Animal Model Animals Area Binding Binding Proteins Biogenesis Biological Models Cardiovascular Diseases Cardiovascular system Cessation of life Chronic Complex Cyclic AMP-Dependent Protein Kinases Data Diabetes Mellitus Diet Disease Drosophila genus Eating Epidemic Eukaryota Event Evolution Explosion Family Food Gene Expression Genetic Genetic Translation Goals Growth Factor Health Health Care Costs Human Human Genetics Insulin Insulin Resistance Insulin-Like Growth Factor I Intervention Invertebrates Investigation Knock-in Mouse Laboratories Lead Link Longevity Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA Metabolism Metformin Modeling Molecular Molecular Profiling Mus Nerve Degeneration Neurodegenerative Disorders Nutrient Nutritional Obesity Organism Pathology Pathway interactions Peptide Initiation Factors Pharmaceutical Preparations Pharmacotherapy Phosphorylation Phosphotransferases Play Polyribosomes Probability Process Production Proline Protein Biosynthesis Protein Kinase Proteins Quality of life Regulation Research Resistance Ribosomal Protein S6 Ribosomal Protein S6 Kinase Ribosomal Proteins Ribosomes Role Signal Pathway Signal Transduction Sirolimus Site Testing Therapeutic Time Translating Translations United States Untranslated Regions Work Yeasts adenylate kinase age related aged arm cell growth cost dietary restriction disorder control fly genetic regulatory protein human FRAP1 protein innovation insulin sensitivity loss of function mTOR protein man mutant novel novel strategies public health relevance research study response success trait treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Obesity is a worldwide epidemic that accounts for more than 300,000 deaths per year in the United States alone. Moreover, it is the major reason behind the explosion in health care costs and the disquieting observation that, for the first time in decades, human life span is decreasing for North Americans. A direct consequence of obesity is the enhanced probability of a number of age-related pathologies including diabetes, cardiovascular disease, neurodegenerative disorders, and cancer. The epidemic has been fueled by the availability, abundance, and relatively low cost of food. The critical barrier in controlling the disease has been the inability to overcome dominant human genetic traits that promote the acquisition of food and the storage of energy reserves in the form of adipose depots. It is hypothesized that these traits were selected for during evolution as a consequence of the chronic scarcity of food and that, over time, they have prevailed over those traits that suppress food intake. Given these limitations and the magnitude of the obesity epidemic, it is critical to develop novel intervention strategies, such as targeted drug therapies. The success of such strategies will depend on a basic understanding of the molecular mechanisms that drive these responses. In contrast, to nutritional overload, dietary restriction is a robust environmental manipulation that increases "healthspan", as it not only prolongs life span but also delays the onset of age-related diseases. Although under intense investigation, the underlying molecular mechanisms that lead to obesity-induced pathologies associated with age-related diseases versus those of dietary restriction-induced increases in healthspan have remained difficult to resolve. Nonetheless, one signaling pathway that has emerged as a major player in both responses is that mediated by mTORC1. Under conditions of nutritional overload, this pathway is fully activated and known to contribute to obesity and insulin resistance. In contrast, under conditions of dietary restriction this signaling pathway is suppressed, which has been demonstrated to contribute to increased healthspan. Importantly, conservation of signaling pathways in simpler eukaryotes and the rapidity with which healthspan studies can be carried out make research in model organisms such as Drosophila invaluable in elucidating healthspan-related diseases in humans. Moreover, studies in different organisms have shown that the nutrient arm of the mTORC1 signaling pathway is highly conserved from yeast to man and is a central mediator of the effect of dietary restriction. S6K1 is a well established downstream target of mTORC1 whose deficiency in the mouse has been shown to increase insulin sensitivity, increase resistance to diet-induced obesity, and increase life span, while sparing animals from much age-related pathology. Several downstream substrates of S6K1 have been identified; however, those mediating healthspan are unknown. We propose that phosphorylation of dS6, the first-identified downstream substrate of S6K1, is an essential player in dietary restriction-mediated healthspan extension. We provide preliminary data to support this novel hypothesis. PUBLIC HEALTH RELEVANCE: Obesity, which has recently become a worldwide epidemic, is well recognized for its deleterious effects on health whereas dietary restriction increases healthspan, as it delays the onset of age- related diseases. The mTORC1/S6K1 signaling pathway has emerged as a major player in both states: under conditions of nutritional overload, this pathway contributes to obesity and insulin resistance while under conditions of dietary restriction it is suppressed and increases healthspan. The proposed project will use Drosophila model and analyze a downstream effector of this signaling pathway, the phosphorylation of S6, to reveal the mechanisms by which it affects dietary restriction mediated healthspan extension.

描述（由申请人提供）：肥胖是一种世界范围内的流行病，仅在美国每年就造成超过 300,000 人死亡。此外，这是医疗保健费用激增以及令人不安的观察背后的主要原因，即北美人的寿命几十年来首次下降。肥胖的直接后果是增加许多与年龄相关的疾病的可能性，包括糖尿病、心血管疾病、神经退行性疾病和癌症。食品的供应、丰富和相对低廉的成本助长了这一流行病。控制这种疾病的关键障碍是无法克服人类显性遗传特征，这些特征促进食物的获取和以脂肪库形式储存能量储备。据推测，这些特征是在进化过程中由于食物的长期匮乏而被选择的，并且随着时间的推移，它们已经战胜了那些抑制食物摄入的特征。鉴于这些局限性和肥胖流行的严重程度，制定新的干预策略（例如靶向药物疗法）至关重要。此类策略的成功将取决于对驱动这些反应的分子机制的基本了解。相比之下，与营养过剩相比，饮食限制是一种强有力的环境操纵，可以延长“健康寿命”，因为它不仅可以延长寿命，还可以延缓与年龄相关的疾病的发生。尽管正在进行深入的研究，但导致肥胖引起的与年龄相关疾病相关的病理与饮食限制引起的健康寿命增加的潜在分子机制仍然难以解决。尽管如此，在这两种反应中已成为主要参与者的一条信号通路是由 mTORC1 介导的。在营养过剩的情况下，该途径被完全激活，并且已知会导致肥胖和胰岛素抵抗。相反，在饮食限制的情况下，该信号通路受到抑制，这已被证明有助于延长健康寿命。重要的是，简单真核生物中信号通路的保守性以及健康寿命研究的快速进行使得对果蝇等模式生物的研究对于阐明人类与健康寿命相关的疾病具有不可估量的价值。此外，对不同生物体的研究表明，mTORC1 信号通路的营养臂从酵母到人类都是高度保守的，并且是饮食限制效应的核心调节因子。 S6K1 是 mTORC1 的一个成熟的下游靶点，在小鼠中，S6K1 的缺乏已被证明可以增加胰岛素敏感性，增强对饮食引起的肥胖的抵抗力，并延长寿命，同时使动物免受许多与年龄相关的病理影响。 S6K1 的几种下游底物已被鉴定；然而，那些调节健康寿命的因素尚不清楚。我们提出，dS6 的磷酸化（第一个确定的 S6K1 下游底物）在饮食限制介导的健康寿命延长中发挥着重要作用。我们提供初步数据来支持这一新颖的假设。公共健康相关性：肥胖最近已成为世界范围内的流行病，众所周知，它对健康有害，而饮食限制则可以延长健康寿命，因为它可以延缓与年龄相关的疾病的发生。 mTORC1/S6K1 信号通路已成为这两种状态的主要参与者：在营养过剩的情况下，该通路会导致肥胖和胰岛素抵抗，而在饮食限制的情况下，该通路会受到抑制并延长健康寿命。拟议的项目将使用果蝇模型并分析该信号通路的下游效应器（S6 的磷酸化），以揭示其影响饮食限制介导的健康寿命延长的机制。