In part due to advances in modern medicine, many of us are living longer, and a greater proportion of the population of the Western world is over 60 than ever before. However, there is reduced benefit to these extra years of life if they are overshadowed by poor health; we want to increase 'healthspan' not 'lifespan'. What determines healthy ageing? What does it mean to die 'of old age' rather than some disease? We do not understand these processes yet. One strong candidate for the maintenance and repair of the body is a specialized cell called the adult stem cell. These differ from the embryonic stem cells that are so often in the press. Whereas embryonic stem cells have the ability to differentiate into any lineage (and become any tissue), the adult stem cell is committed to repairing and regenerating the tissue in which it resides. It achieves this by i, activating in response to cues, such as injury ii, proliferating, providing a pool of cells that will repair the damage and iii, through one of these cell divisions, replacing itself for future use. In the elderly, the ability of adult stem cells to perform these functions in markedly reduced, leading to gradual tissue deterioration. A good exemplar of this is skeletal muscle. After the age of 50, skeletal muscle mass declines by ~10% per decade; muscle also becomes weaker and contains more fat. On the positive side, studies in animals have determined that the decline in muscle adult stem cell (called the 'satellite' cell) behavior in ageing is not due to defects within the cell itself but is rather because the cell does not receive the correct signals from its environment. The overall aim of this project is to examine the theory that a key signaling molecule, called p38 MAPK, has a key role in interpreting these signals from the environment and dictating the way in which satellite cells subsequently behave; it therefore acts as a 'gateway'. p38 regulates many of the important events in muscle satellite cell activation, ranging from stopping cells dividing to changing the genes that are activated and therefore the proteins that the cell can make. If p38 is activated too soon, adult stem cells will not have sufficient opportunity to form enough cells for repair and replacement. We will address the following specific questions: 1) Does increased p38 activity restrict the 'choices' of muscle satellite cells? What would happen if p38 activity were suppressed? We will answer this by generating mice that lack p38 in adult muscle stem cells (knockout mice). We expect that they may produce increased numbers of precursor cells. 2) What are the first stages by which p38 regulates gene expression? DNA does not exist as a naked strand but is rather wound around groups of proteins called histones (the whole unit is called chromatin). Histones can be modified by the addition of methyl groups; it is now believed that these modifications ultimately change the shape of chromatin, either making it compact and inaccessible to molecules that will encourage gene expression (transcription factors), or 'opening' the chromatin so that transcription factors can function. We will examine two fundamental histone modifications, which regulate each of these events. 3) What are the signals that control p38 activation? Some of these will come from outside the cell, and some from inside. We will increase or decrease the activity of candidate regulators and determine the consequences for p38 activity and satellite cell function. 4) Most important, what changes occur in p38 activity during ageing? What happens if we prevent p38 activation in muscle satellite cells from old animals? We will test this using the knockout mice made in point 1. We predict that the normal decrease in satellite cell activation and proliferation that occurs in old mice will be ameliorated in the p38 knockout mice. This may prevent part of the decline in muscle mass that occurs in ageing.

Axons are the long fibres that connect one nerve cell with another and carry electrical communication between them. If these fibres degenerate, nervous function ceases resulting in neurodegenerative diseases such as Alzheimer's disease, motor neuron disease and multiple sclerosis. In many nervous disorders, the degeneration of the fibres precedes death of the cell from which they arise, but in the central nervous system the fibres cannot regenerate even if the cell survives. Thus, it is essential to understand and eventually intervene in axon degeneration mechanisms. We have identified a gene that can delay axon degeneration tenfold in mice, rats and flies, and have now found a chemical treatment that blocks its action. The aim of this project is to understand the basis of this block, and to shed light on how one part of a nerve cell signals to other parts that damage has taken place.

Work in this Theme provides an unprecedented opportunity for this grouping of PIs and for the national and international scientific community to establish reference epigenomes for the key stages of epigenetic reprogramming and programming in germ cells, preimplantation embryos, and lineage commitment in early postimplantation embryos. This resource together with the development of an integrated epigenomics database will underpin the biological exploration of epigenetic reprogramming mechanisms, the unravelling of signalling principles that pattern the epigenome during development and ageing, and the understanding of how non-coding RNAs regulate the epigenome. This resource will become available to the national and international community through established high quality links (eg EU Network of Excellence, IHEC) and will be of great value not only for the epigenetics community, but also for developmental biologists, geneticists, reproductive and evolutionary biologists, stem cell researchers, and those working on the biology of ageing

In a normally functioning neuron, the cell body has to supply its axon with all the materials it needs to keep it healthy. This complex logistical process breaks down completely after injury and often becomes compromised in neurodegenerative diseases. When this happens, the isolated axon degenerates. Whilst isolated axons clearly will not be able to exist indefinitely without replenishment of many important cargoes delivered from the cell body, those that are short-lived will be depleted first, so loss of short-lived proteins is likely to act as a stimulus for degeneration. Using clues from a mutant mouse whose axons are protected from degeneration, we have identified delivery of Nmnat2, a protein with an important enzyme activity, as a limiting factor for axon survival. Importantly, Nmnat2 is very short-lived and its levels decline rapidly in injured axons before they start to degenerate. Without it, even uninjured axons degenerate by a similar mechanism, consistent with loss of this protein being a natural stimulus for axon degeneration. This is likely to have important therapeutic implications. The aims of this project are to understand how the Nmnat2 survival molecule is delivered to axons by the sophisticated molecular machinery in axons, that transports molecules over distances up to a metre long. Like any supply chain, this one dimensional delivery of protein is vulnerable to blockage and axonal degeneration, leading to diseases such as motor neuron disease and Alzheimer’s disease. If we can deliver more of this protein into axons and keep it stable for longer we may be able to delay or prevent such diseases.

When our lungs are invaded by viruses and bacteria, our immune system sends white blood cells to the site, which 'eat' and destroy the invaders. Unfortunately, the weapons that white blood cells use to kill bacteria can sometimes also damage our own lung tissue. This damage can cause diseases like Acute Respiratory Distress Syndrome (ARDS) and Bronchiectasis. At the moment, this process is not well understood and we have no strategies for preventing it. We have been studying a protein in the lungs, known as a small GTPase. We have genetic evidence that this protein has an important role in cells that are a major cause of ARDS. Mice that don't have the protein are perfectly able to fight infections from things like bacteria, but do not experience any associated lung damage. This suggests that this protein is involved in the process that damages lung tissue. This research aims to understand how our immune system attacks the lungs in this way. In so doing the researchers will make advances to prevent such damage. This grant from The British Lung Foundation is to determine whether this signalling mediator is potentially a good target for drugs to fight ARDS. Anti-inflammatory drugs available to treat lung disease are currently very non-specific, affecting many cell types and usually preventing the beneficial effects of white cells in fighting infection. Such drugs (e.g. corticosteroids) thus have many side effects including increased susceptibility to infection. By finding and understanding a new signaling pathway, we hope to identify possible drug targets that may limit inflammation without leading to increased risk of infection. This research may thus lead to novel treatments for ARDS and other inflammatory lung diseases.