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Cellular mechanisms governing nutrient sensing and organismal energy homeostasis

控制营养感应和有机体能量稳态的细胞机制

基本信息

批准号：
10673609
负责人：
Akhila Rajan
金额：
$ 42.68万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-11 至 2027-07-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY From bacteria to humans, organisms modulate their food intake and energy expenditure in accordance with their internal nutrient state, allowing them to maintain a healthy energy balance. During evolution, conserved homeostatic mechanisms developed to cope with potential nutrient deprivation from a fluctuating food supply. Hence, when food is plentiful, excess energy is stored as fat reserves and mobilized during future scarcity. However, in the 21st-century nutritional scarcity is the exception rather than the norm, resulting in an increasing prevalence of obesity in humans. Obesity impacts cancer progression, accelerates aging, compromises immunity, and impedes a healthy lifestyle. We posited that understanding mechanisms and molecules at the interface of opposing nutrient states — scarcity and surplus — will reveal processes that control critical metabolic outcomes. Furthermore, we proposed that certain proteins function as molecular switches to control processes that allow an organism to operate in both states efficiently. We further surmised that chronic nutrient surplus impairs the capacity of the ‘molecular switch’ proteins to efficiently alternate in response to the nutritional state, resulting in energy imbalance. Once we identified such proteins, we determined to use them as an entry point to identify cellular mechanisms critical to healthy energy balance. To this end, we investigated one process: how do fat cells retain or release fat hormones – called adipokines— that serve as systemic nutrient surplus signals? Our investigations led to identifying one critical molecular switch, which is recognized as playing a role in membrane fusion events in previous studies. However, unexpectedly, we identified that this protein controls nutrient-state-dependent adipokine intracellular localization and gene expression. Therefore, we have uncovered a molecular switch mechanism that controls unanticipated cellular processes at the intersection of scarcity and surplus. The cellular processes that we have uncovered represent strategic avenues to treat and manage complex metabolic disorders. Hence, we propose to elucidate the following: i) define the molecular pathway by which this molecular switch protein controls nucleocytoplasmic localization and gene expression; ii) understand how diet-induced obesity disrupts this regulation, and iii) map consequences of this cell-intrinsic mechanism to organism-level metabolic outcomes and behaviors. We will use fruit flies for short to medium-term goals, as we have established a robust physiological Drosophila surplus model that mimics the diseased state. We will test conservations of these findings in mammalian systems in the future. In summary, our goal is to address outstanding issues in energy physiology by adopting a comprehensive and conceptually novel approach in a highly tractable model.

项目摘要从细菌到人类，生物体根据其自身的行为调节其食物摄入和能量消耗。内部营养状态，使他们保持健康的能量平衡。在进化过程中，为了科普波动的食物供应可能造成的营养缺乏而发展的自我平衡机制。因此，当食物充足时，多余的能量作为脂肪储备储存起来，并在未来的短缺中动员起来。然而，在21世纪，营养短缺是例外而不是常态，导致越来越多的肥胖症在人类中的流行。肥胖影响癌症进展，加速衰老，免疫力，阻碍健康的生活方式。我们假设，了解机制和分子在相反的营养状态的界面-稀缺和过剩-将揭示控制关键代谢的过程结果。此外，我们提出，某些蛋白质作为分子开关来控制过程使生物体在两种状态下都能有效运作。我们进一步推测慢性营养过剩削弱了“分子开关”蛋白质响应营养状态而有效交替的能力，导致能量不平衡。一旦我们确定了这样的蛋白质，我们决定将它们作为切入点，确定健康能量平衡的关键细胞机制。为此，我们研究了一个过程：脂肪细胞是否保留或释放脂肪激素-称为脂肪因子-作为系统营养过剩的信号？我们的研究导致确定一个关键的分子开关，这是公认的发挥作用，膜融合事件。然而，出乎意料的是，我们发现这种蛋白质控制着营养状态依赖性脂肪因子细胞内定位和基因表达。因此，我们发现一种分子开关机制，在稀缺性和顺差我们发现的细胞过程代表了治疗和管理的战略途径复杂的代谢紊乱因此，我们建议阐明以下内容：i）通过以下方式定义分子途径：该分子开关蛋白控制核质定位和基因表达; ii）理解饮食诱导的肥胖如何破坏这种调节，以及iii）绘制这种细胞内在机制的后果，生物体水平的代谢结果和行为。我们将使用果蝇作为短期到中期的目标，已经建立了一个强大的生理果蝇盈余模型，模仿疾病状态。我们将测试这些发现在哺乳动物系统中的保存在未来。总之，我们的目标是解决在能量生理学中的突出问题，通过采用全面和概念新颖的方法，高度易处理模型。