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

描述(申请人提供)：肥胖是一种世界性流行病，仅在美国每年就导致30多万人死亡。此外，这也是医疗费用激增的主要原因，也是数十年来北美人的寿命首次出现下降这一令人不安的现象。肥胖的一个直接后果是增加了一些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。食品的可获得性、丰富性和相对较低的价格助长了这种流行病。控制这种疾病的关键障碍一直是无法克服人类的显性遗传特征，这些特征促进了食物的获取和以脂肪库的形式储存能量。据推测，这些特征是在进化过程中被选中的，作为长期食物稀缺的结果，随着时间的推移，它们已经压倒了那些抑制食物摄入的特征。鉴于这些局限性和肥胖症流行的严重性，开发新的干预策略至关重要，例如靶向药物疗法。这些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，对于营养过重来说，饮食限制是一种强有力的环境操纵，可以增加“健康寿命”，因为它不仅延长了寿命，还推迟了与年龄有关的疾病的发生。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导致的健康寿命延长的潜在分子机制仍然很难解决。尽管如此，在这两种反应中扮演主要角色的一个信号通路是由mTORC1介导的。在营养过载的情况下，这一途径被完全激活，并已知会导致肥胖和胰岛素抵抗。相比之下，在饮食限制的条件下，这一信号通路被抑制，这已被证明有助于延长健康寿命。重要的是，在更简单的真核生物中信号通路的保守性和进行健康跨度研究的速度使得在果蝇等模式生物中的研究对于阐明人类健康跨度相关疾病是非常有价值的。此外，在不同生物中的研究表明，mTORC1信号通路的营养臂从酵母到人类是高度保守的，是饮食限制效应的中心调节因子。S6K1是mTORC1下游的一个成熟靶点，其在小鼠中的缺乏已被证明可以增加胰岛素敏感性，增加对饮食诱导的肥胖的抵抗力，并延长寿命，同时使动物免于许多与年龄相关的病理。已经确定了S6K1的几种下游底物；然而，那些调节健康跨度的底物尚不清楚。我们认为，作为首次发现的S6K1下游底物，DS6的磷酸化在饮食限制介导的健康延长中起着重要的作用。我们提供了支持这一新假说的初步数据。 公共卫生相关性：肥胖最近成为一种世界性流行病，人们普遍认为它对健康的有害影响，而限制饮食则延长了健康时间，因为它推迟了与年龄有关的疾病的发病。MTORC1/S6K1信号通路在这两种状态下都扮演着重要的角色：在营养超负荷的情况下，这一通路有助于肥胖和胰岛素抵抗，而在饮食限制的条件下，这一通路被抑制，并延长健康寿命。该项目将使用果蝇模型，并分析该信号通路的下游效应物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。

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.