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: 9751087
• 负责人: Akhila Rajan
• 金额: $ 44万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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/9751087
• 关键词: Acute; Address; Adopted; Aging; Anorexia; Bacteria; Biological; Biological Models; Cancerous; Cell Death; Cells; Chronic; Communication; Diabetes Mellitus; Disease; Drosophila genus; Eating; Energy Metabolism; Evolution; Fatty acid glycerol esters; Food; Food Energy; Food Supply; Future; Generations; Goals; Health; Human; Immune; Immunity; Intervention; Investigation; Maintenance; Malignant Neoplasms; Mechanics; Modeling; Molecular; Nerve Degeneration; Nutrient; Nutritional; Obesity; Organ; Organism; Overnutrition; Pathway interactions; Pharmacologic Substance; Physiological; Physiology; Prevalence; Proliferating; Proteins; Scientist; Signal Transduction; Stress; System; Testing; Therapeutic; Time; Virus; Work; design; energy balance; healthy lifestyle; impaired capacity; interest; novel strategies; nutrient deprivation; response; tumor progression

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.

项目摘要： 从细菌到人类，有机体根据其食物摄入和能量消耗调节 它们的内部营养状态，可以维持健康的能量平衡。在进化中保守 稳态机制开发出来，以应对粮食供应波动的潜在营养剥夺。 因此，当食物充足时，多余的能量被存储为脂肪储量，可以在 未来的稀缺。但是，在21世纪，营养短缺是例外，而不是常态，导致 在人类肥胖的越来越多。肥胖会影响癌症的进展 神经变性，加速衰老并阻碍健康的生活方式。以前，许多研究 专注于生物如何应对营养稀缺性，并导致进化的阐明 保守的机制，策划了对食物稀缺性的反应。我们的目标是了解相反的 营养状态，通过关注生物如何应对慢性“过度营养”。我们希望这些 机制将是短距离，急性，局部细胞生物学变化，并且时间尺度延长 器官系统的身体反应。那遥远，我们确定了先前未表征的剩余信号传导 成分。出乎意料的是，我们发现分子对于稀缺反应至关重要，也是关键调节剂 营养盈余。鉴于剩余的储存进化为生存未来营养的保护策略 稀缺性，可能会携带一组重叠的分子来使生物感知和反应 到这两个互斥状态。以我们的观察为前提，我们假设一套 “双向”开关蛋白夫妇的差异和剩余机制，使生物可以在之间切换 根据需要。我们进一步浏览了慢性营养盈余，这种状态在进化过程中很少见， 损害这种“双向分子开关”的能力有效地替代营养 状态，导致能量失衡。我们的短期目标是a）编纂分子套件的基础 双向营养开关； b）确定有助于器官间的新的双向营养开关 能量平衡所需的沟通。然后，在中期，我们将c）系统剖析 在经历慢性营养盈余时，双向机制降低并失去可塑性。最后，我们的 长期目标是d）制定针对双向分子套件的药物干预措施，并 测试它们在恢复营养压力的系统中的能量平衡方面的作用。基本 我们从这项工作中得出的原则将阐明分子成分如何设计在某个特定中发挥作用 可以选择生理状态以实现拮抗反应。从我们的原则中获得的原则 研究将适用于了解病毒如何劫持免疫细胞或解释如何取消细胞 欺骗细胞死亡通路和过度散热。最终，我们的目标是解决能源的杰出问题 生理学，在高度可牵引的模型中采用全面且概念上的新方法。