The molecular and cellular mechanisms that trigger and sustain a regenerative response

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Lay summaryThe simple act of living comes with a constant barrage of potential risks, often arising as injuries, which can be either minor or traumatic. In addition, many diseases also are the result of or are responsible for impaired tissue function. Finally ageing is generally associated with diminished tissue integrity and function. The emerging field of regenerative medicine aims to ameliorate all of these consequences and repercussions of life by identifying novel means of repairing injured, diseased and aged tissues, with the ultimate aim of promoting full restoration of their original functions. In this way, this field hopes to extend the healthy lifespan of humans. Given that risks of injury, disease and ageing are not limited to humans, we can sometimes turn to other organisms and ask how do they deal with injuries? More importantly we can sometimes turn to organisms that are much better at repairing their tissues following injury and ask how and why do they exhibit such remarkable regenerative capacities? And finally, can we hope to learn enough from them so that we may be able to mimic their high regenerative capacity with the aim of significantly improving our ability to repair and regenerate tissue in the future? This is exactly what we aim to do in our research. We have recently been exploiting the remarkable capacity of amphibian tadpoles to fully regenerate their tails and limbs following amputation. As part of our studies, we recently discovered that frog tadpoles produce compounds while they regenerate that are normally thought of as damaging to cells. These compounds are collectively referred to as reactive oxygen species (ROS), and include such molecules as hydrogen peroxide, which at relatively high concentrations is used to bleach hair and to kill bacteria. Our findings were particularly interesting in that they showed that frog tadpoles not only produced these compounds following tail amputation, but we also showed that they had to produce these compounds in order for them to be able to regenerate their tails.. We went on to show that, if we did not allow the tadpoles to produce these compounds, the cells in their amputated tails were no longer able to proliferate as normal and they were no longer able to signal to each other as normal. These findings form the basis for this proposal. Here we wish to ask the following questions:1. How does injury trigger the production of ROS following tail amputation in frog tadpoles?2. What are the mechanisms that control the level of ROS, such that it does not rise too high, or remain too low for regeneration to proceed?3. Which genes are controlled by ROS production?4. How does ROS levels affect the way cells signal each other during regeneration?5. Is the production of ROS also required for the regeneration of other appendages, such as limbs and fins, and if so, are the mechanisms similar amongst different organisms?Answering these questions will help us gain a deeper insight into how sustained ROS production promotes regeneration, and whether this role is conserved across different animals. Ultimately we hope that our study will pave the way towards the development of novel therapies aimed at promoting tissue repair and regeneration in human patients, where regenerative potential is normally limiting.