Hypoxia and the control of protein synthesis and homeostasis in Drosophila

果蝇缺氧与蛋白质合成和稳态的控制

• 批准号: RGPIN-2016-04544
• 负责人: Grewal, Savraj
• 金额: $ 3.93万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=652471
• 关键词: Hypoxia; control; protein; synthesis; homeostasis

Animals often live in conditions where environmental oxygen levels fluctuate As a result, they must coordinate their metabolism with changes in oxygen availability. In particular, upon oxygen deprivation, or hypoxia, animals need to alter their metabolism to limit energetically costly anabolic processes, maintain homeostasis and promote survival. Defects in this metabolic control can impair cell and tissue homeostasis and can lead to lethality.******One metabolic strategy is suppression of protein synthesis. Given that protein synthesis accounts for over a third of cellular ATP use, this suppression helps to restrict energy expenditure. Selective translational control also provides a mechanism to limit gene expression to proteins required for stress responses. Hypoxia can suppress translation and the mechanisms have been studied almost exclusively in cell culture. What is not clear is how translational control contributes to in vivo regulation of cell and tissue homeostasis in animals during hypoxia. ******The goal of this NSERC program is to examine how hypoxia regulates mRNA translation to control organismal physiology and survival, using Drosophila as a model. Drosophila can tolerate prolonged periods of low oxygen with no effects on viability. Our program has three main objectives to examine the molecular basis for this striking hypoxia tolerance:***Objective 1: To examine the effects of PERK on hypoxia tolerance. Our data suggest that hypoxia suppress translation by activating PERK kinase, which phosphorylates and inhibits eIF2alpha, an essential translation initiation factor. Moreover, we find that PERK mutants are unable to tolerate hypoxia. We will test whether PERK exerts these effects on translation and organismal survival via cell autonomous and /or cell non-autonomous mechanisms.******Objective 2: To examine effects of PERK on insulin signaling in hypoxia. Suppression of insulin signaling is a conserved regulatory response to stress in invertebrates. We find that hypoxia inhibits systemic insulin signaling in Drosophila. We will test whether this is a mechanism used by PERK to regulate hypoxia tolerance. ******Objective 3: To identify new regulators of hypoxia tolerance. This longer-term objective will use polysome profiling to identify genes whose mRNA translation is induced by hypoxia. We will then investigate these genes as potential regulators of hypoxia tolerance. These objective will provide new, long-term avenues of investigation for our program.******This NSERC grant will establish a new, exciting program of research to help understand how cells, tissues and organisms can tolerate hypoxia and maintain homeostasis and survival. ********

动物通常生活在环境氧气水平波动的环境中，因此它们必须协调自己的新陈代谢和氧气供应的变化。特别是，在缺氧或缺氧的情况下，动物需要改变他们的新陈代谢，以限制耗费能量的合成代谢过程，保持动态平衡，促进生存。这种代谢控制的缺陷会破坏细胞和组织的动态平衡，并可能导致死亡。一种代谢策略是抑制蛋白质合成。鉴于蛋白质合成占细胞ATP使用量的三分之一以上，这种抑制有助于限制能量消耗。选择性翻译控制也提供了一种机制，将基因表达限制在应激反应所需的蛋白质上。低氧可以抑制翻译，其机制几乎只在细胞培养中研究过。目前尚不清楚的是，在低氧状态下，翻译控制如何在动物体内调节细胞和组织的稳态。*这个NSERC项目的目标是以果蝇为模型，研究低氧如何调节信使核糖核酸的翻译，从而控制机体的生理和生存。果蝇可以耐受长时间的低氧，对生存能力没有影响。我们的计划有三个主要目标来研究这种显著的低氧耐受的分子基础：*目标1：检查PERK对低氧耐受的影响。我们的数据表明，低氧通过激活PERK激酶来抑制翻译，PERK激酶使eIF2α磷酸化并抑制eIF2α，eIF2α是一种重要的翻译启动因子。此外，我们发现PERK突变体不能耐受低氧。我们将测试PERK是否通过细胞自主和/或细胞非自主机制在翻译和生物生存中发挥这些作用。*目标2：检测PERK在低氧条件下对胰岛素信号的影响。抑制胰岛素信号是无脊椎动物对应激的一种保守的调节反应。我们发现低氧抑制了果蝇的全身性胰岛素信号转导。我们将测试这是否是PERK用来调节耐缺氧的机制。*目标3：寻找新的耐缺氧调节因子。这个较长期的目标将使用多聚体图谱来识别其mRNA翻译是由低氧诱导的基因。然后，我们将研究这些基因作为耐缺氧的潜在调节因子。这些目标将为我们的计划提供新的、长期的研究途径。*NSERC的这笔拨款将建立一个新的、令人兴奋的研究计划，以帮助了解细胞、组织和有机体如何耐受低氧并维持动态平衡和生存。********