Investigating how cellular mechanisms interface to maintain energy balance

项目摘要：报告 生物体，从细菌到人类，都按照下列规律调节食物摄入量和能量消耗 他们体内的营养状态，允许维持健康的能量平衡。在进化过程中保守 动态平衡机制是为了应对不断变化的食物供应带来的潜在营养匮乏而开发的。 因此，当食物充足时，多余的能量被储存为脂肪储备，这些脂肪可以在 未来的稀缺。然而，在21世纪，营养匮乏是例外，而不是常态，结果是 肥胖在人类中的流行程度越来越高。肥胖影响癌症的进展和 神经退化，加速衰老，阻碍健康的生活方式。此前，一些研究表明， 专注于生物体如何应对营养匮乏，并导致了进化的阐明 协调应对粮食短缺的保守机制。我们的目标是理解相反的情况 营养状态，通过关注生物体如何对长期的“过度营养”做出反应。我们预计这些 其机制既有短期的、急性的、局部的细胞生物学变化，也有延长时间尺度的、间歇性的 器官系统的生理反应。到目前为止，我们确定了以前未描述的剩余信令 组件。出乎意料的是，我们发现了对稀缺性反应至关重要的分子，也是关键的调节因素 营养过剩。鉴于储存剩余物已演变为一种保护策略，以求在未来的营养环境中生存 稀缺性，很可能是一组重叠的分子被用来允许有机体感知和反应 这两个相互排斥的国家。根据我们的观察，我们假设一套 “双向”开关蛋白将稀缺和过剩机制结合在一起，使生物体能够在 根据需要选择两个。我们进一步推测，慢性营养过剩在进化过程中是一种罕见的状态， 削弱这种“双向分子开关”对营养的反应能力 状态，造成能量不平衡。我们的短期目标是a)编纂支撑 双向营养开关；b)确定促进器官间双向营养开关的新的双向营养开关 能量平衡所需的通信。然后，在中期内，我们将c)系统地剖析 当长期营养过剩时，双向机制会退化并失去可塑性。最后，我们的 长期目标是d)开发针对双向分子套件的药物干预措施，以及 在营养紧张的系统中测试它们在恢复能量平衡方面的效果。最基本的 我们从这项工作中得出的原理将阐明分子组件如何在特定的 可以利用生理状态来实现对抗性反应。这些原则是从我们的 研究将适用于理解病毒如何劫持免疫细胞，或解释癌细胞如何 诡计细胞死亡途径和过度增殖。最终，我们的目标是解决能源领域的突出问题 生理学，通过采用全面和概念新颖的方法，在一个高度易处理的模型中。

Project Summary:  Organisms, from bacteria to humans, modulate their food intake and energy expenditure in accordance with their internal nutrient state, allowing for maintenance of healthy energy balance. During evolution conserved homeostatic mechanisms developed to cope with potential nutrient deprivation from a fluctuating food supply. Hence when food was plentiful the excess energy is stored as fat reserves, which can be mobilized during a 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 progression of cancer and neurodegeneration, accelerates aging and impedes a healthy lifestyle. Previously, a number of studies focused on how organisms respond to nutritional scarcity, and have resulted in elucidation of evolutionarily conserved mechanisms that orchestrate a response to food scarcity. Our aim is to understand the opposite nutritional state, by focusing on how organisms respond to chronic ‘over-nutrition’. We expect that these mechanisms will be both short-range, acute, local cell biological changes and also prolonged time-scale, inter- organ systemic physiological responses. Thus far, we identified previously uncharacterized surplus signaling components. Unexpectedly we found molecules that are critical for scarcity responses, are also key regulators of nutritional surplus. Given that storage of surplus evolved as a protective strategy to survive future nutritional scarcity, it is likely that an overlapping set of molecules is employed to allow organisms to sense and respond to these two mutually exclusive states. Premised on our observations, we hypothesize that a suite of ‘bidirectional’ switch proteins couple scarcity and surplus mechanisms, allowing organisms to toggle between the two as needed. We further surmise that chronic nutrient surplus, a state that was rare during the evolution, impairs the capacity of this ‘bidirectional molecular switch’ to efficiently alternate in response to nutritional state, resulting in energy imbalance. Our short-term goal is to a) codify the molecular suite underpinning the bidirectional nutritional switch; b) identify new bidirectional nutrient switches that facilitate inter-organ communication required for energy balance. Then, in the medium-term we will c) systematically dissect how the bidirectional mechanisms degrade and lose plasticity when subject to chronic nutrient surplus. Finally, our long-term goal is to d) develop pharmaceutical interventions that target the bidirectional molecular suite, and test their effect in restoring energy balance in systems that have been nutritionally stressed. The fundamental principles we derive from this work will illuminate how molecular components designed to function in a certain physiological state can be co-opted to achieve an antagonistic response. The principles garnered from our studies will be applicable to understanding how viruses hijack immune cells, or explain how cancerous cells trick cell-death pathways and over-proliferate. Ultimately our goal is to address outstanding issues in energy physiology, by adopting a comprehensive and conceptually novel approach, in a highly tractable model.