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: 10224827
• 负责人: Akhila Rajan
• 金额: $ 42.05万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224827
• 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.

项目概要： 从细菌到人类，生物体都按照以下方式调节其食物摄入和能量消耗： 他们的内部营养状态，允许维持健康的能量平衡。在进化过程中， 为了科普波动的食物供应可能造成的营养缺乏而发展的自我平衡机制。 因此，当食物充足时，多余的能量以脂肪储备的形式储存起来，这些脂肪可以在一段时间内被调动起来。 未来的稀缺性然而，在21世纪世纪，营养短缺是例外而不是常态， 肥胖症的发病率越来越高。肥胖影响癌症的进展， 神经退化，加速衰老，阻碍健康的生活方式。此前，一些研究 集中在生物体如何应对营养短缺，并导致阐明了进化 保守的机制，协调对粮食短缺的反应。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应对慢性“过度营养”。我们预计这些 机制将是短范围的，急性的，局部细胞生物学变化，以及延长的时间尺度， 器官系统的生理反应。到目前为止，我们发现了以前未表征的盈余信号 件.出乎意料的是，我们发现了对稀缺反应至关重要的分子，也是关键的调节器， 营养过剩。考虑到储存剩余的食物是一种保护性的策略， 由于缺乏，很可能是一组重叠的分子被用来让生物体感知和反应， 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”开关蛋白结合了稀缺和过剩机制，使生物体能够在 两人根据需要。我们进一步证实，长期营养过剩，一种在进化过程中罕见的状态， 削弱了这种“双向分子开关”的能力，以有效地改变对营养的反应， #21453;，造成能源不平衡。我们的短期目标是a）编纂支撑生物学的分子套件， 双向营养开关; B）识别促进器官间营养的新的双向营养开关; 能源平衡所需的通信。然后，在中期，我们将c）系统地剖析如何 当受到慢性营养过剩时，双向机制退化并失去可塑性。最后我们 长期目标是d）开发靶向双向分子组的药物干预，以及 测试它们在恢复营养紧张系统中的能量平衡方面的作用。根本 我们从这项工作中得出的原则将阐明分子组件是如何在某种特定的环境中发挥作用的。 生理状态可以被增选以实现拮抗反应。我们的原则 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 欺骗细胞死亡途径并过度增殖。我们的最终目标是解决能源方面的突出问题 生理学，通过采用全面的和概念新颖的方法，在一个高度易处理的模型。