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）：肥胖是一种全球流行病，仅在美国，每年就会占30万多人。此外，这是医疗保健成本爆炸式爆炸背后的主要原因，以及令人不安的观察结果，即几十年来，北美人的生命跨度首次减少。肥胖的直接后果是多种与年龄有关的病变的可能性提高，包括糖尿病，心血管疾病，神经退行性疾病和癌症。食物成本的可用性，丰度和相对较低的食物为助长了流行病。控制这种疾病的关键障碍是无法克服促进食物获取和以脂肪仓库形式促进能量储备的占主导地位的人类遗传特征。假设这些特征是由于食物的慢性稀缺而在进化过程中选择的，并且随着时间的流逝，它们已经占了上那些抑制食物摄入量的特征。鉴于这些局限性和肥胖症流行的大小，制定新颖的干预策略，例如靶向药物疗法至关重要。这种策略的成功将取决于对推动这些反应的分子机制的基本理解。相比之下，对于营养超负荷，饮食限制是一种强大的环境操纵，可以增加“ HealthSpan”，因为它不仅延长了寿命，而且还延迟了与年龄有关的疾病的开始。尽管经过激烈的研究，但导致与年龄相关疾病相关的肥胖引起的病理学的潜在分子机制与饮食限制引起的HealthSpan增加的病理仍然难以解决。尽管如此，在这两种响应中都出现了一个主要参与者的信号通路是由MTORC1介导的。在营养超负荷的条件下，该途径被充分激活，并已知有助于肥胖和胰岛素抵抗。相反，在饮食限制的条件下，该信号通路被抑制，这已被证明会导致健康范围的增加。重要的是，在更简单的真核生物中保存信号通路，以及可以进行健康范围研究的速度，使在诸如果蝇等模型生物中进行研究，在阐明人类中与健康范围有关的疾病中无价之宝。此外，在不同生物体中的研究表明，MTORC1信号通路的营养臂从酵母到人都高度保守，并且是饮食限制作用的核心调解人。 S6K1是MTORC1的一个良好确定的下游靶标，其缺乏在小鼠中可提高胰岛素敏感性，增加对饮食诱导的肥胖症的耐药性，并增加寿命，同时使动物从与年龄相关的病理学中释放。已经确定了S6K1的几个下游基板；但是，那些介导的健康范围是未知的。我们建议DS6的磷酸化是S6K1的第一个识别下游底物，是饮食限制介导的HealthSpan扩展的重要参与者。我们提供初步数据以支持这一新假设。公共卫生相关性：最近已成为全球流行病的肥胖症因其对健康的有害影响而闻名，而饮食限制会增加健康状况，因为它延迟了与年龄相关的疾病的开始。 MTORC1/S6K1信号传导途径在两种状态下都成为主要参与者：在营养超负荷的条件下，该途径在饮食限制的条件下有助于肥胖和胰岛素抵抗，在饮食限制的条件下受到抑制并增加了健康状态。拟议的项目将使用果蝇模型，并分析该信号传导途径的下游效应子S6的磷酸化，以揭示其影响饮食限制介导的Healthspan扩展的机制。