Identification and characterisation of novel hydroxylases and their substrates involved in cellular hypoxic response.

人体能够感知并响应氧气水平的变化。在低氧（缺氧）条件下，单个细胞会开启许多不同的基因，以增加红细胞的产生和血流量，并减少耗氧量。这可能是在高海拔等环境条件下发生的，但也是许多人类疾病的重要组成部分，如心脏病发作和中风（血栓阻止血液流动和氧气输送）或癌症（肿瘤需要氧气生长）。我们已经知道一些关键蛋白质被缺氧激活，如HIF蛋白质，这些蛋白质作为一个主开关打开许多其他基因。然而，实际的氧传感器仍然是一个谜。我和其他人最近的研究已经确定了一些氧传感器，它们是需要氧气的羟化酶。在氧气充足的正常条件下，它们修饰HIF蛋白并使其保持非活性，但当氧气有限时，它们不能修饰HIF，未修饰的HIF是活性的。到目前为止，已经确定了四种不同的氧传感器，但有强有力的证据表明还有更多的传感器，它们可能会改变更多的目标，而不仅仅是HIF。该项目旨在确定新的氧传感羟化酶和新的靶标，并确定它们各自的作用。我已经有了一些初步的信息，关于其他一些氧气传感器可能是什么，以及它们可能的目标。这项工作应该大大提高我们对身体如何应对缺氧的理解，无论是在正常条件下还是在疾病期间。这些氧传感器也可能是非常有用的药物靶点。例如，抑制这些酶的药物应该增加HIF蛋白的活性，并促进身体对心脏病发作或中风的更快反应，从而限制损害，而激活酶的药物将抑制HIF并有助于限制肿瘤生长。

The human body is able to sense and respond to changes in oxygen levels. Under low oxygen (hypoxia) individual cells switch on a number of different genes required to increase red blood cell production and blood flow, and decrease oxygen consumption. This may be under environmental situations such as high altitude, but is also an important part of many human diseases, such as heart attack and stroke (where a clot stops blood flow and oxygen delivery) or cancer (where tumours require oxygen for growth). We have known for sometime that a few key proteins are activated by hypoxia, such as the HIF proteins, and these act as a master switch to turn on numerous other genes. However, the actual oxygen sensors have remained a mystery. Recent research by others and myself has identified a number of the oxygen sensors, which are hydroxylase enzymes that require oxygen. Under normal conditions with ample oxygen they modify the HIF proteins and keep them inactive, but when oxygen is limiting they can't modify the HIFs and the unmodified HIF is active. So far four different oxygen sensors have been identified, but there is strong evidence for more sensors, and they are likely to modify more targets than just the HIFs. This project aims to identify new oxygen sensing hydroxylases and novel targets, and determine what they each do. I already have some preliminary information as to what some of the other oxygen sensors might be and also some of their likely targets. This work should greatly enhance our understanding of how the body responds to hypoxia, both under normal conditions and during disease. These oxygen sensors might also be very useful drug targets. For example, drugs that inhibit these enzymes should increase the activity of the HIF proteins and facilitate a more rapid response by the body to a heart attack or stroke, and thus limit the damage, whereas drugs that activate the enzymes would inhibit the HIFs and be useful in limiting tumour growth.