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

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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.