World-class bioscience investment at University of Leicester

The University of Leicester has been awarded over £1.5million in order to advance knowledge and understanding in three key areas that impact on health.

The funding has come from the Biotechnology and Biological Sciences Research Council (BBSRC), which leads world-class 21st century bioscience, promoting innovation in the bioeconomy and realising benefits for society within and beyond the UK. BBSRC support around 1600 scientists and 2000 research students in universities and institutes across the UK.

Three groups from the University of Leicester have won awards. They are led by:

• Professor David Lambert, £338,432, Department of Cardiovascular Sciences
• Professor Marco Rinaldo Oggioni £700,532 Department of Genetics
• Dr Shaun Cowley £507,945 Department of Molecular and Cell Biology

The projects cover a wide range of subjects that impact on human health, including sepsis; the spread of infections and cancer amongst other things

Professor Lambert, from the Department of Cardiovascular Sciences, and his team have designed a novel 'biosensor' to observe the release of nociceptin from single living immune cells - this has never been done before.

He said: "This is a really exciting project from understanding the basics of release at the single cell level to translation into a disease relevant model; sepsis. Sepsis is a huge problem taking 31,000 lives and costing the UK NHS some £2Billion per year; treatment options are limited. BBSRC funding is critical to understanding the basics of the process that will underpin clinical development."

Professor Oggioni from the Department of Genetics, is investigating the spread of infection. He said: "This will give us a better understanding of the means by which pathogenic bacteria spread to us either through food or from animals and is expected to have clear benefit in the prevention of infection and will possibly also have impact on antimicrobial drug resistance."

Dr Cowley from the Department of Molecular and Cell Biology said: "My colleague, Prof Schwabe, and I work on a class of enzymes called HDACs (histone deacetylases) which help regulate access to the information stored within our DNA. Drugs which inhibit HDACs can prevent cancer cells from growing, reduce inflammation and have positive effects on models of Alzheimer's disease. Despite these promising results, we still don't really understand how they work at a molecular level. Our project grant from the BBSRC is designed to understand how the cell signals to HDAC enzymes and fine-tunes their activity."

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We are interested in a peptide member of opioid (other opioids include morphine and heroin) family called nociceptin that controls pain in the nervous system. In the cardiovascular system this peptide also dilates blood vessels and slows the heart. Outside the nervous system nociceptin can be produced by immune cells (circulating white blood cells) and we know very little about how this happens. We have designed a 'biosensor' that will allow us to measure the release of nociceptin. Using this novel biosensor it will be possible to observe the release of nociceptin from single living immune cells; this has never been done before. We hope to be able to determine which type(s) of immune cells are responsible for release and to understand what is controlling the process. We know that nociceptin is important in immune related diseases, in particular sepsis and we hope to be able to translate this work to gain a better understanding. Blood pressure changes are a feature of sepsis and this might be explained in part by effects on the nociceptin system.

All the cells of a species contain the same DNA; what distinguishes them is the way in which that DNA is activated ('transcribed'). One method of regulating DNA transcription is through direct chemical modification of the DNA itself, most commonly through a process of methylation. This is termed 'epigenetic' regulation. There has been extensive study of epigenetic regulation in humans and other complex life forms, but comparatively little in bacteria. Bacterial genomes are often extensively methylated, as a consequence of 'restriction modification' (RM) systems, which modify the cell's DNA at particular sites to allow it to be distinguished from the DNA of infecting viruses. The many sites of methylation across the genome have the potential to substantially affect the way in which genes are regulated. However, as most RM systems are stable and therefore cannot serve as a regulatory mechanism. This is not the case for two sets of genes we have recently independently characterised in the bacterium Streptococcus pneumoniae, the pneumococcus. The pneumococcus is a commensal bacterium, typically carried by between a quarter and a third of young children asymptomatically, that is a major cause of diseases including middle ear infections, pneumonia and meningitis. The sets of genes we found are RM systems that vary over the course of hours or days through a specific set of DNA rearrangements. This results in the patterns of methylation caused by the RM systems also changing over short timescales. Experimental data found that different forms of the inverting RM system caused different patterns of methylation, each of which was associated with a distinct pattern of gene expression. This epigenetic regulation of bacterial genes was found to change the virulence of the bacterium, with some patterns of methylation making the pneumococcus more likely to cause disease. This could be an important factor in the transition from the pneumococcus being a harmless commensal, to becoming a dangerous pathogen. This project is designed to test this hypothesis through studying whether the second variable RM system in the pneumococcus affects the same processes, or has a different effect on cell physiology, and whether such systems regulate the virulence of other pathogenic bacteria. Searching of the thousands of publically available bacterial DNA sequences has allowed us to identify hundreds of species that harbour similar systems. These include bacterial species that are very common in the human gut, some that are present in probiotic drinks and others involved in the production of cheese. Perhaps most importantly, they are also present in many pathogenic bacteria. This project is designed to investigate whether these variable RM systems might also regulate virulence in three bacterial species that each represent major threats to public health. The first is Streptococcus suis, a species normally associated with pigs that is emerging as a major pathogen capable of causing serious infections, such as meningitis. The second is Listeria monocytogenes, a foodborne bacterium that causes potentially fatal infections. The third is Enterococcus faecalis, a major cause of highly antibioticresistant infections, particularly in a hospital setting. In the three species, the variable RM loci are present with lineages that are associated with causing high levels of disease in humans, and absent from those that are asymptomatically found in animals or humans. The overall aim of the project is to work out how these systems may play a role in regulating genes involved in the bacteria's virulence, as well as how they evolved and how diverse they are. Such information will allow us to understand why these unusual genes are distributed, and why bacteria progress from being harmlessly carried to causing disease. This would better inform our strategies as to how to prevent this transition, and thereby tame these common, but potentially dangerous, bacteria.

'Histone deacetylase' (HDAC) enzymes are present in all cells of the body. Their function is to switch genes 'off', and make sure they stay 'off'. In many respects shutting a gene down is every bit as important as switching a gene on. HDAC enzymes represent an exciting medical opportunity because they are 'druggable'. Already, drugs which inhibit HDAC activity are being used in the clinic as anti-cancer agents, and in the laboratory for their beneficial effects on dementia and anti-inflammatory properties. There is therefore a compelling applied, as well as academic, motivation for studying their physiological roles in order to assess their potential as pharmacological targets. We use a technique called 'X-ray crystallography' which allows us to determine the shape and structure of HDAC enzymes at a molecular level. Once we have determined their shape it allows us to understand the way that HDACs bind to other proteins and small molecules such as inositol phosphate (IP). We recently showed in vitro (i.e. in a test tube) that the enzymatic activity of HDACs was dependent upon the binding of IP. Following on from this discovery, the purpose of this project is to understand the importance of IP to HDAC function in cells and in mice. To do this we have three main objectives: 1) We plan to generate cells with low, medium and high levels of IP and test whether these correlate with level of HDAC activity. 2) In cells, HDACs interact with other proteins to form a multi-protein 'complex'. The complex most sensitive to the presence of IP is called, MIDAC and it consists of three proteins bound together (HDAC1, DNTTIP1 and MIDEAS). To understand the regulation of HDAC complexes by IP we plan to solve the structure of MIDAC using X-ray crystallography. 3) The role of MIDAC in cells is completely unknown and so we aim characterize the physiological activity of MIDAC, using cells lacking one of the three members of the complex, DNTTIP1. By understanding the molecular basis of HDAC complex function we can use that knowledge to design new drugs to prevent them from working. The ability to stop HDACs from working has beneficial effects on a wide-range of diseases, including epiplepsy, bipolar dissorder and Alzheimer's disease, making them excellent drug targets.

The Biotechnology and Biological Sciences Research Council (BBSRC) invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by Government, BBSRC invested over £509M in world-class bioscience in 2014-15. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

For more information about BBSRC, our science and our impact see: http://www.bbsrc.ac.uk

For more information about BBSRC strategically funded institutes see: http://www.bbsrc.ac.uk/institutes