Roles of hypothermia in response to environmental hypoxia: Behavioural and thermal modulation of the genetic and proteomic responses to low oxygen

低温在环境缺氧反应中的作用：遗传和蛋白质组对低氧反应的行为和热调节

• 批准号: NE/D010845/1
• 负责人: Mark Viney
• 金额: $ 51.87万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NE%2FD010845%2F1
• 关键词: Roles; hypothermia; response; environmental; hypoxia

We will conduct the first investigation of the interdependence of hypoxia (low oxygen) induced gene expression and behavioural hypothermia. The work is best carried out in ectothermic animals, whose body temperature changes with that of the environment. We will use an invasive pest crayfish, Pacifastacus leniusculus, which is displacing the endangered native species. When faced with lowered environmental oxygen such species seek out a cooler environment, thereby lowering metabolic rate and oxygen demand. Normal physiological responses to hypoxia include underlying changes in gene expression and protein profiles. This gene transcription is regulated by a hypoxia inducible factor (HIF) which is normally degraded if sufficient oxygen is present. We will examine the exciting possibility that behavioural induced hypothermia can modulate gene expression by reducing tissue oxygen demand. Recent and tantalising evidence indicates that metabolites of energy metabolism may regulate a coordinated response in gene transcription and behaviour, or even that behaviour is a result of changes in gene expression. We will collaborate with Dr Gorr/Prof Gassmann (Zurich). The aim is to show how behaviour may modulate gene expression or, alternatively, is coordinated with gene expression. We will characterise the hypoxic gene response and the resulting changes in the protein profile of the tail muscle of animals in low oxygen, compared to normal oxygen, and determine if lowered body temperature obviates this gene and protein response. We will probe the linkage between behaviour and hypoxia induce gene transcription by a pharmacological approach. Using inhibitors that block HIF degradation, even in normoxic cells, we will establish dependent responses in; (a) gene transcription, (b) protein profiles and (c) behaviour. This latter point is near unique since it uses behaviour as assay of gene expression. We will use exogenous inhibitors (not natural to the animal) of HIF degradation, as well as metabolites of energy metabolism which inhibit HIF degradation and putatively stimulate the behaviour. Thus, effects of metabolites that promote cold-seeking behaviour and induce hypoxia responsive genes will link the two responses. Effects of exogenous compounds, that stimulate behaviour will do so as a consequence of changes in the expression of hypoxia responsive genes, that is behaviour is promoted by changed gene expression. The study will reveal if energy metabolism feeds back directly on genes in response to hypoxia and if this is modulated by behaviour. The potential implications range from environmental to biomedical. The HIF system is a target for tumour treatment and evidence as to the role of temperature and metabolites of energy metabolism is directly relevant. Should we prove that the behavioural and molecular responses to hypoxia are separate (behaviour delays the molecular response), there will be large ecological significance for animals with access to cooler habitats. Should we prove that behaviour and molecular responses are linked by metabolic signals or that behaviour is caused by molecular events then this will open new areas of ecological, environmental and biomedical investigation. Discovering new feedback (or feed-forward) systems in physiological and behavioural responses has implications for understanding species success, temporal costs in protein turnover, and the behaviour of cells, be they tumour cells or from environmentally stressed animals. Hypoxia is an important environmental factor limiting the distribution and success of aquatic species (e.g. eutrophication of rivers and lakes). The likelihood for any species survival depends significantly on the nature and extent of the hypoxic response. Variation in this response between species can lead to changes in the faunal mix, which may be of relevance for P. leniusculus in our study since it is displacing the native species, in part, due a greater hardiness and survivorship.

我们将首次研究缺氧（低氧）诱导的基因表达和行为性低温的相互依赖性。这项工作最适合在变温动物身上进行，它们的体温会随着环境的变化而变化。我们将使用一种入侵性害虫小龙虾，Pacifastacus leniusculus，它正在取代濒临灭绝的本地物种。当面临环境氧气降低时，这些物种会寻求凉爽的环境，从而降低代谢率和需氧量。对缺氧的正常生理反应包括基因表达和蛋白质谱的潜在变化。该基因转录受缺氧诱导因子 (HIF) 调节，如果存在足够的氧气，该因子通常会被降解。我们将研究行为诱导的低温可以通过减少组织需氧量来调节基因表达的令人兴奋的可能性。最近诱人的证据表明，能量代谢的代谢物可能调节基因转录和行为的协调反应，甚至该行为是基因表达变化的结果。我们将与戈尔博士/加斯曼教授（苏黎世）合作。目的是展示行为如何调节基因表达，或者与基因表达协调。我们将与正常氧气相比，描述低氧环境下动物尾部肌肉蛋白质谱的低氧基因反应以及由此产生的变化，并确定体温降低是否会消除这种基因和蛋白质反应。我们将通过药理学方法探讨行为与缺氧诱导基因转录之间的联系。使用阻止 HIF 降解的抑制剂，即使在含氧量正常的细胞中，我们也将在以下方面建立依赖性反应： (a) 基因转录，(b) 蛋白质谱和 (c) 行为。后一点几乎是独特的，因为它使用行为作为基因表达的测定。我们将使用 HIF 降解的外源抑制剂（对动物来说不是天然的），以及抑制 HIF 降解并推测刺激行为的能量代谢代谢物。因此，促进寻冷行为和诱导缺氧反应基因的代谢物的作用将把这两种反应联系起来。刺激行为的外源化合物的作用是由于缺氧反应基因表达的变化而产生的，也就是说，行为是通过改变基因表达来促进的。该研究将揭示能量代谢是否直接反馈到基因以应对缺氧，以及这是否受到行为的调节。潜在影响范围从环境到生物医学。 HIF 系统是肿瘤治疗的靶点，温度和能量代谢代谢物的作用的证据是直接相关的。如果我们证明对缺氧的行为和分子反应是分开的（行为延迟了分子反应），那么对于能够进入较凉爽栖息地的动物来说将具有巨大的生态意义。如果我们证明行为和分子反应是通过代谢信号联系起来的，或者行为是由分子事件引起的，那么这将为生态、环境和生物医学研究开辟新的领域。在生理和行为反应中发现新的反馈（或前馈）系统对于理解物种的成功、蛋白质周转的时间成本以及细胞的行为（无论是肿瘤细胞还是来自环境压力的动物）具有重要意义。缺氧是限制水生物种分布和成功的重要环境因素（例如河流和湖泊的富营养化）。任何物种生存的可能性很大程度上取决于缺氧反应的性质和程度。物种之间这种反应的变化可能会导致动物群混合的变化，这可能与我们研究中的 P. leniusculus 相关，因为它正在取代本地物种，部分原因是其具有更强的抗寒性和生存能力。