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.

项目总结(如家长资助金所述) 生物体，从细菌到人类，根据它们的能力调节食物的摄入量和能量消耗 体内营养状态，可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，一些研究集中在 关于生物体如何对营养匮乏做出反应，并导致阐明进化上的保守 协调应对粮食短缺的机制。我们的目标是了解相反的营养状态， 通过关注生物体如何对长期的“过度营养”做出反应。我们预计这些机制将既是 短期的、急性的、局部的细胞生物学变化以及延长的时间尺度、器官间系统变化 生理反应。到目前为止，我们确定了以前未描述的剩余信号组件。 出乎意料的是，我们发现了对稀缺性反应至关重要的分子，它们也是营养的关键调节因素 盈余。考虑到储存剩余物是为了在未来的营养匮乏中生存下来的一种保护性策略，它是 很可能是一组重叠的分子被用来允许有机体感知并对这两个分子做出反应 相互排斥的国家。基于我们的观察，我们假设一套“双向”开关 蛋白质将稀缺和过剩机制结合在一起，使有机体能够根据需要在两者之间切换。我们 进一步推测，慢性营养过剩，一种在进化过程中罕见的状态，削弱了 这种‘双向分子开关’可以根据营养状态有效地交替，从而产生能量 不平衡。我们的短期目标是a)编纂支持双向营养开关的分子套件； B)确定新的双向营养开关，以促进能量所需的器官间通信 平衡。然后，在中期内，我们将c)系统地剖析双向机制如何退化 并在长期营养过剩的情况下失去可塑性。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，并测试它们在恢复能量方面的效果 营养压力过大的系统的平衡。我们从这项工作中得出的基本原则 将阐明设计用于在特定生理状态下发挥作用的分子组件如何被增选 以达到对抗性的反应。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，或者解释癌细胞如何欺骗细胞死亡途径和过度增殖。 归根结底，我们的目标是通过采用全面和 概念上的新方法，在一个高度易处理的模型中。