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: 10386531
• 负责人: Akhila Rajan
• 金额: $ 12.5万
• 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/10386531
• 关键词: Acute; Address; Adopted; Aging; Bacteria; Biological; Biological Models; Blood - brain barrier anatomy; Brain; Cancerous; Cell Death; Cells; Chronic; Communication; Drosophila genus; Eating; Energy Metabolism; Evolution; Fatty acid glycerol esters; Food; Food Energy; Food Supply; Future; Goals; Hormones; Human; Immune; Immunity; Intervention; Investigation; Lipids; Maintenance; Modeling; Molecular; Nerve Degeneration; Neurons; Nutrient; Nutritional; Obesity; Organ; Organism; Overnutrition; Pathway interactions; Pharmacologic Substance; Physiological; Physiology; Prevalence; Proliferating; Proteins; Scientist; Signal Transduction; Stress; System; Testing; Time; Virus; Work; adipokines; design; energy balance; healthy lifestyle; impaired capacity; interest; novel strategies; nutrient deprivation; parent grant; particle; response; tumor progression

Project Summary (AS STATED IN PARENT GRANT) 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（如父母赠款所述） 从细菌到人类的生物体，根据他们的食物摄入和能量消耗 内部营养状态，允许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，许多研究集中 关于生物如何应对营养稀缺性，并导致阐明进化保存 协调对食物稀缺的回应的机制。我们的目的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，还延长了时间尺度的组织间全身性 身体反应。那远，我们确定了先前未表征的剩余信号传导组件。 出乎意料的是，我们发现对稀缺反应至关重要的分子也是营养的关键调节剂 剩余。鉴于剩余的存储是发展为生存未来营养短缺的受保护策略的，这是 可能会携带一组重叠的分子，以使生物感知并响应这两个 相互排斥的国家。以我们的观察为前提，我们假设一套“双向”开关 蛋白质使稀缺性和剩余机制融为一体，使生物可以根据需要在两者之间进行切换。我们 进一步推测，长期养分盈余（在进化过程中很少见）损害了能力 这种“双向分子开关”有效地响应营养状态，导致能量 不平衡。我们的短期目标是a）编纂双向营养开关的分子套件； b）确定新的双向营养开关 平衡。然后，在中期，我们将系统剖析双向机制如何降解 并在经历长期养分盈余时失去可塑性。最后，我们的长期目标是d）发展 针对双向分子套件的药物干预措施，并测试其恢复能量的作用 营养压力的系统平衡。我们从这项工作中得出的基本原则 将阐明如何选择以某种物理状态功能的分子成分 达到拮抗反应。从我们的研究中获得的原则将适用于理解 病毒如何劫持免疫细胞，或解释取消细胞如何欺骗细胞死亡途径和过度裂解。 最终，我们的目标是通过采用全面和 在高度易于处理的模型中，概念上新颖的方法。