Final Report Summary - EXTREMOPHILE MAMMAL (Molecular exploitation of an extremophile mammal) In this project the broad aim was to identify molecular features of the naked mole-rat that contribute to various aspects of its extreme physiology. The naked mole-rat displays many unusual physiological features e.g. insensitivity to pain, extreme longevity, an inability to generate bodily heat (cold blooded like a lizard) and an apparently very high resistance to cancer. In this project we focused on some of these extreme attributes, firstly we examined the insensitivity of the naked mole-rat to several substances that cause pain in other mammals including man. The naked mole-rat does not become more sensitive to painful stimuli after injury, a phenomenon called hyperalgesia (or pain hyper sensitivity after injury). In the course of these studies we could identify changes in a the naked mole-rat version of signalling molecule called TrkA that appear to lead to lack of pain hypersensitivity, particularly heat pain in the naked mole-rat. We changed the mouse TrkA gene to resemble that of the naked mole-rat to tune down pain hypersensitivity in the mouse. These studies demonstrate how molecular changes in the naked mole-rat can be re-engineered into another species like the mouse to make the physiology of the mouse resemble that of the mole-rat. In the course of these studies we also examined the pain sensitivity of several mole-rat species that live underground and are close African relatives of the naked mole-rat. We found that several of these unconventional rodent species were insensitive to one of three substances that normally cause an acute pain reaction in other species (the so called algogens acid, capsaicin the active ingredient of chilli peppers and AITC which is the active ingredient of pungent Wasabi). We used modern genomic techniques to sequence and quantify the levels of more than 6000 genes in 7 African rodents. This analysis allowed us to identify many genes that had either undergone changes in sequence or level to facilitate pain insensitivity. This study showed how environmental pressure can lead to a loss of pain sensitivity in nature and that we can use modern molecular techniques to identify the molecular changes that reduce pain sensitivity. In a second part of the study we were very interested in how the naked mole-rat can deal with reduced levels of oxygen that occur regularly as a part of its normal lifestyle. Naked mole-rats are eusocial meaning that just one female in sometimes very large colonies ( up to 300 animals) is able to breed (like Bees and Termites). We noticed that our naked mole-rat coonies all sleep in large pile simultaneously every day and obviously many animals, at the bottom of the pile, may be very starved of oxygen under these circumstances. Together with our collaborator Thomas Park we found that naked mole-rats have a very high tolerance for lack of oxygen. They can live and thrive in just 5% oxygen (compared to 20% in normal air) and can survive complete oxygen deprivation for up to 18 minutes. In this project we showed how the naked mole-rat can survive repeated periods of oxygen deprivation. In order to survive the heart and brain tissue must be able to generate energy to keep cells alive without using oxygen so called anaerobic respiration. The naked mole-rat tissues switch to using fructose instead of glucose to fuel anaerobic respiration when oxygen levels fall. We could show that fructose can drive anaerobic respiration much more efficiently and reliably than glucose. This mechanism may still exist in other mammals like mice and humans but it has been greatly expanded in the naked mole-rat. These data revealed a new molecular trick used by the naked mole-rat to avoid tissue damage when oxygen levels fall. In the Western world heart failure and stroke a huge problems that are due to irreversible tissue damage that follows lack of oxygen delivery to the heat and brain. It may be that the naked mole-rat can gives us clues on how to avoid such damage due to oxygen loss.