Investigating how cellular mechanisms interface to maintain energy balance

研究细胞机制如何相互作用以维持能量平衡

• 批准号: 10642109
• 负责人: Akhila Rajan
• 金额: $ 1.95万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10642109
• 关键词: Investigating; how; cellular; mechanisms; interface

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.

项目概要： 从细菌到人类，生物体根据以下方式调节食物摄入和能量消耗： 它们的内部营养状态，允许在进化过程中保持健康的能量平衡。 体内平衡机制的发展是为了应对食物供应波动造成的潜在营养匮乏。 因此，当食物充足时，多余的能量就会以脂肪储备的形式储存起来，可以在一段时间内被调动起来。 然而，在 21 世纪，营养短缺是例外，而不是常态。 人类肥胖患病率不断增加，肥胖会影响癌症的进展。 此前有多项研究表明，神经退行性疾病会加速衰老并阻碍健康的生活方式。 重点研究生物体如何应对营养匮乏，并从进化角度阐明了 我们的目标是了解相反的机制。 营养状态，通过关注生物体如何应对慢性“营养过剩”，我们期望这些。 机制既是短程的、急性的、局部的细胞生物学变化，也是长时间尺度的、相互间的变化。 到目前为止，我们发现了以前未表征的剩余信号传导。 出乎意料的是，我们发现对稀缺反应至关重要的分子也是关键的调节因子。 鉴于储存剩余营养是为了在未来的营养中生存的一种保护策略。 稀缺性，很可能采用一组重叠的分子来让生物体感知和响应 以我们的观察为前提，我们捕捉到了这两种相互排斥的状态。 “双向”开关蛋白将稀缺和过剩机制结合起来，允许生物体在两者之间切换 我们进一步推测，长期营养过剩，这种状态在进化过程中是罕见的， 损害这种“双向分子开关”有效交替响应营养的能力 状态，导致能量失衡。我们的短期目标是 a) 编纂支撑该状态的分子套件。 双向营养转换；b) 识别新的促进器官间营养转换的双向营养转换 然后，在中期我们将 c) 系统地剖析如何实现。 当长期营养过剩时，双向机制会退化并失去可塑性。 长期目标是开发针对双向分子套件的药物干预措施，以及 测试它们在恢复营养紧张的系统中的能量平衡方面的效果。 我们从这项工作中得出的原理将阐明分子组件如何设计以在特定的功能中发挥作用 可以选择生理状态来实现拮抗反应。 研究将适用于了解病毒如何劫持免疫细胞，或解释癌细胞如何 最终我们的目标是解决能源领域的突出问题。 通过在高度易于处理的模型中采用全面且概念新颖的方法来研究生理学。