Evolution of Oxygen Sensing in Animals

我们提议做的工作是基于我们对人类感知氧气方式的了解。调节氧气向组织的输送对于所有将其用作能量来源的生物体来说都是一个问题，特别是对于由数十亿个细胞和不同类型组织组成的大型动物如人类来说更是如此。许多人类疾病，如心脏病发作、中风、癌症和贫血，都涉及低氧水平（缺氧）对细胞和组织功能的损害。在以前的工作中（其中的重要组成部分得到了BBSRC的支持），我们已经确定了一组加氧酶（催化将大气中的氧掺入其底物的酶），它们通过催化称为HIF（缺氧诱导因子）的蛋白质中特定氨基酸残基的羟基化（包括添加氧原子）来充当细胞的“氧传感器”。羟基化破坏并灭活HIF，但由于它需要氧气，这种反应在缺氧中受到抑制，使HIF在缺氧细胞中被激活（因此得名）。缺氧诱导因子是一种转录因子（基因表达的调节因子），当打开时，它会调节许多基因，这些基因参与改变细胞代谢、生长新血管、增加血液产量以及帮助身体在缺氧中生存的其他作用。这些发现开辟了一个新的研究领域，研究这种类型的蛋白质修饰，它做什么，它如何受到缺氧的调节，以及它如何影响细胞对缺氧的反应。关于HIF的工作也提出了许多问题，即这种类型的修饰（羟基化）是否发生在细胞内的其他类型的蛋白质上，以及可能的影响。最近，我们发现HIF系统也存在于最简单的生活在海洋中的动物粘毛藻中。我们的初步数据表明，Trichoplax氧传感系统与人类系统密切相关，但要简单得多，主要是因为Trichoplax的基因组比人类小得多。我们的目的是进行详细的比较人类和Trichoplax HIF系统，以调查是否HIF或相关的氧传感系统存在于其他生物。我们最初的数据表明，HIF存在于所有动物中，但不存在于动物进化而来的生物体（领鞭毛虫）中，这使我们提出HIF系统沿着氧气水平和多细胞动物的上升而进化，或者就在生命进化中著名的前寒武纪时期之前。在大卫·阿滕伯勒（David Attenborough）最近播出的电视连续剧《第一次生命》（First Life）中，对进化的这一方面进行了优雅的描述。然而，我们还发现，尽管HIF不存在，但与HIF羟化酶相关的酶也存在于细菌中。我们认为这些酶在原核生物中通过一种未知的机制具有氧传感作用，并最终进化为人类的氧传感酶。因此，我们的工作最终旨在将分子和基因组分析与进化研究联系起来。然而，根据我们的经验，跨物种分析可以更深入地了解人类细胞如何工作的潜在机制-由于人类细胞生物学的复杂性，这些机制通常很难剖析。最后，虽然我们的工作将使用无脊椎动物，但它们的细胞生物学和胚胎发育方面似乎与人类细胞保持良好，这提高了它们可能有助于在药物开发中取代哺乳动物的可能性。

The work we are proposing to do is based on insights we have obtained into the way humans sense oxygen. Regulating the delivery of oxygen to tissues is a problem for all organisms that use it as an energy source and particularly so for large animals such as humans that are composed of many billions of cells and different types of tissues. Many human diseases such as heart attacks, strokes, cancer, and anaemia involve damage to cell and hence tissue function by low oxygen levels (hypoxia). In previous work (important components of which were supported by the BBSRC) we have identified a group of oxygenases (enzymes that catalyse the incorporation of atmospheric oxygen into their substrates) that act as cellular 'oxygen sensors',by catalysing the hydroxylation (involving addition of an oxygen atom) of specific amino acid residues in a protein called HIF (hypoxia inducible factor). Hydroxylation destroys and inactivates HIF, but since it requires oxygen, this reaction is suppressed in hypoxia, allowing HIF to become activate in hypoxic cells (hence its name). HIF is a transcription factor (a regulator of gene expression) that, when switched on, regulates many genes that are involved in altering cell metabolism, growing new blood vessels, increasing blood production and other actions that help the body to survive hypoxia. These findings have opened up a new field of research on this type of protein modification, what it does, how it is regulated by hypoxia, and how it affects the cell's responses to hypoxia. The work on HIF has also raised many questions as to whether this type of modification (hydroxylation) occurs for other types of protein within cells, and what the effects might be. Recently, we have found that the HIF system also exists in the simplest living animal, Trichoplax adhaerens, which lives in the sea. Our initial data suggest that the Trichoplax oxygen sensing system is closely related to the human system, but is much simpler, largely because Trichoplax has a much smaller genome than humans. We aim to carry out a detailed comparison between the human and Trichoplax HIF systems, to investigate whether the HIF or related oxygen sensing systems exist in other organisms. Our initial data suggests that HIF is present in all animals but not in the group of organisms from which animals are though to have evolved (choanoflagellates), leading us to propose that the HIF system evolved along with the rises in oxygen levels and multicellular animals, at or just before the famous Precambrian period in the evolution of life. This aspect of evolution has been elegantly described in the recent television series 'First Life' presented by David Attenborough. However, we have also found that enzymes related to the HIF hydroxylases also exist in bacteria even though HIF doesn't. We think that these enzymes had an oxygen sensing role via an unknown mechanism in prokaryotes, and eventually evolved into the human oxygen sensing enzymes. Our work thus ultimately aims to connect molecular and genomic analyses with evolutionary studies. However, it is our experience that the cross-species analyses can lead to deeper understanding of the underlying mechanisms of how human cells work - these are often difficult to dissect because of the complexity of human cell biology. Finally, although our work will employ the use of invertebrates, aspects of their cell biology and embryonic development appear to be well conserved with human cells, raising the possibility that they may contribute to the replacement of mammals in drug development.