Evolution of Oxygen Sensing in Animals

我们计划做的工作是基于我们对人类感知氧气的方式所获得的见解。对于所有将氧气用作能源的有机体来说，调节氧气向组织的输送是一个问题，尤其是对人类等由数十亿个细胞和不同类型的组织组成的大型动物来说。许多人类疾病，如心脏病发作、中风、癌症和贫血，都涉及到低氧水平(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(催化大气中的氧结合到其底物中的酶)，通过催化一种名为HIF(缺氧诱导因子)的蛋白质中特定氨基酸残基的羟化(涉及氧原子的添加)来充当细胞‘氧感应器’。羟化作用破坏和失活HIF，但由于它需要氧气，这一反应在低氧条件下被抑制，允许HIF在低氧细胞中激活(因此而得名)。HIF是一种转录因子(基因表达的调节器)，当启动时，它调节许多基因，这些基因涉及改变细胞新陈代谢、生长新血管、增加血液产量和帮助身体在低氧中生存的其他行动。这些发现为这种蛋白质修饰开辟了一个新的研究领域，包括它的作用，它如何受到低氧的调节，以及它如何影响细胞对低氧的反应。对HIF的研究也提出了许多问题，如细胞内其他类型的蛋白质是否会发生这种类型的修饰(羟化)，以及影响可能是什么。最近，我们发现HIF系统也存在于生活在海洋中的最简单的生物--粘毛藻中。我们的初步数据表明，Trichoplax氧气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。我们的目标是在人类和Trichoplax HIF系统之间进行详细的比较，以调查HIF或相关的氧气传感系统是否存在于其他生物体中。我们的初步数据表明，HIF存在于所有动物中，但不存在于被认为是动物进化的有机体(脊椎动物)中，这导致我们提出，HIF系统是随着氧气水平和多细胞动物的上升而进化的，在生命进化中著名的前寒武纪时期或之前。在大卫·艾登堡最近播出的电视连续剧《第一生命》中，对进化的这一方面进行了优雅的描述。然而，我们也发现细菌中也存在与HIF羟基酶相关的酶，我们认为这些酶在原核生物中通过一种未知的机制起到氧感应作用，并最终进化成人类的氧感应酶。因此，我们的工作最终目的是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，跨物种分析可以加深对人类细胞如何工作的潜在机制的理解--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，尽管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的某些方面似乎与人类细胞保存得很好，这增加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.