Leicester University: The pursuit of excellence

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The human body consists of billions of cells, each one doing a specific job but working together with others to carry out specific tasks. An understanding of how cells, tissues and organs function in health, and what happens to them in disease, is critical to our understanding of heart attacks, hypertension and anxiety, to name a few. Research does not get much more fundamental than this…

The University of Leicester is leading the way in medical research to combat life-threatening illnesses and diseases. Exciting new research programmes in the Department of Cell Physiology and Pharmacology (CPP) are investigating a range of diseases in an attempt to identify potential new targets and therapies.

Professor Andrew Tobin and his team in CPP, are engaged in cutting edge medical research that aims to tackle the scourge of cancer.

They recently won prestigious funding for the third time for research on a family of proteins that respond to many commonly used drugs, such as beta-blockers for heart disease, salbutamol inhalers for the treatment of asthma and Zantac for the treatment of ulcers. His current Wellcome Trust Senior Research Fellowship is worth £1.3M over 5 years, and his research has brought in the order of £3M in grant income since 1996.

Professor Tobin and his team are examining a family of cell surface proteins that they believe could play a critical role in targeting cancer cells. The proteins, G-protein coupled receptors (GPCRs), exist in hundreds of different types. Said Professor Tobin: “When we are frightened, and our hear beats faster, this is because adrenaline activates one type of GPCR in the heart.”

Professor Tobin said it was possible to target specific cells in the body because different GPCRs present on the target cells can be activated or inhibited by specific drugs.

“When a GPCR is stimulated, there is an explosion of activity in the cell that results in the cell contracting, releasing hormones, moving or conducting an electrical current. It is as if the flood gates have been opened. It is our aim to harness this activity in the development of new anti-cancer drugs. By stimulating the correct GPCRs on cancer cells we aim to change the activity of the cell in a way that helps chemotherapeutic drugs to work specifically on the cancer cells. Understanding GPCRs as gateways to the activity of a cell will help in the design of these new anti-cancer drugs.”

The incredible diversity of GPCRs means that they play a role in a number of medical problems. Dr Christine Pullar, a New Blood Lecturer appointed only recently, has just won a research grant valued at £260,000 from the Wellcome Trust to investigate potential treatments for chronic wounds such as bed sores and diabetic ulcers.

A major problem is that chronic wounds heal with difficulty due to their poor blood supply and this can be extremely debilitating for our ageing population. Dr Pullar has discovered that activation or blockade of a GPCR, the ß2-adrenoceptor, can modify healing. Dr Pullar’s research will help to unravel the complex mechanisms controlling blood vessel formation, hopefully leading to new avenues of treatment for chronic wounds.

Following this diabetes theme, Terry Herbert, a Senior Lecturer in the department, was recently awarded a £222,454 grant from the Wellcome Trust to study how glucose regulates the activity of a protein called PERK and its role in pancreatic beta cell function/dysfunction. The results obtained from this study will lead to a better understanding of the mechanisms involved in the development of diabetes and provide leads for new therapies.

Cardiovascular diseases such as stroke, hypertension and heart attack, are amongst the most common killers in the western world and are a key research interest in the department. An internationally recognised research grouping that includes Professor Nick Standen, Professor Richard Evans, Professor Martyn Mahaut-Smith, Professor John Challiss, Dr John Mitcheson, Dr Noel Davies, Dr Steve Ennion, Dr Catherine Vial and Dr Nina Storey, is engaged in a number of research projects that seek to understand a range of cardiovascular diseases.

Professor Richard Evans has just received a second renewal of his Wellcome Trust funded programme grant (£1.1 million) to investigate how receptors for ATP, an important metabolite, contribute to the development of cardiovascular diseases. These receptors, called P2X1 receptors, are found on arteries and platelets (the cells involved in control of bleeding) and drugs that block these receptors are potentially useful in the treatment of high blood pressure and blood clotting associated with stroke. To predict any possible side effects of P2X1 receptor drugs it is important to understand any other biological functions the receptors may have.

Above, left to right, Professors Nicholas Hartell and Martyn Mahaut-Smith

Below, British Heart Foundation-funded research using the platelet precursor cell, the megakaryocyte, is investigating cellular events that may contribute to thrombosis. Fluorescent indicators show the structure of invaginating surface membranes (green) and nucleus (magenta) of a bone marrowderived megakaryocyte. Image by Martyn Mahaut-Smith.

Professor Martyn Mahaut-Smith, who recently joined CPP from the University of Cambridge, is interested in the mechanisms by which platelets are produced and their roles in health and in disease. Martyn’s work has already led to a patent for the development of novel antithrombotic agents and he is also continuing a longstanding collaboration with Richard Evans to understand the role of individual subtypes of P2 receptor in the clotting process.

Professor Nick Standen, together with colleagues, was recently awarded a British Heart Foundation programme grant valued at £690,308 to investigate the mechanisms by which proteins, called Kv, that regulate the flow of potassium ions out of smooth muscle cells influence constriction in the walls of small arteries. These channel proteins are themselves regulated by hormones and the study will look at how signals such as blood glucose regulate this process.

The British Heart Foundation has also funded two major projects for new members of staff in CPP. Dr Nina Storey will look at the mechanisms by which the KATP protein helps to protect against ischaemic heart attacks. Dr Catherine Vial’s project will investigate how mast cells contribute to the development of fatty plaques and then clots in blood vessels. If these clots dislodge then this can lead to a heart attack or a stroke, two of the biggest causes of death in the western world.

The brain is the least well understood of all our organs due to its enormous complexity and the huge amount of connectivity between cells. Who would have thought to look to a creature living at the bottom of the garden, the humble garden snail, to provide remarkable insights into the workings of the human brain?

In research funded by the Biotechnology and Biological Sciences Research Council to the tune of £322,000, Dr Volko Straub is hoping that these snails will provide an insight into the development of the human mind.

His study could also help us to understand how a gas, nitric oxide, plays an important role in learning. Dr Straub explained. “During brain development, nitric oxide can promote the growth of nerve cells and the formation of connections between nerve cells. Learning also triggers the formation of new connections between nerve cells and in many cases requires nitric oxide.

“However, studying these processes in higher animals is complicated by the complexity of their nervous system. Fortunately, evolution has been very conservative and the basic processes and factors that control the growth of nerve cells and the formation of functional connections are highly conserved in all animals. So, we decided to use the nervous system of the common pond snail, which is considerably less complex than the nervous system of higher animals such as mice, as a model system.”

This research may also lead to a greater understanding of the development of the nervous system and the processes that control nerve cell regeneration following injury.

Closely related research into the cellular mechanisms of memory storage is being carried out by Professor Nick Hartell, a recent appointment to the department. Memory is thought to be encoded as long lasting changes in the strength of signalling between synapses formed by excitable cells in the brain. By gaining a better understanding of the mechanisms responsible for memory acquisition, Professor Hartell’s team, funded by the BBSRC, aim to improve our ability to enhance the brain’s capacity to learn and develop strategies for repair following injury or neurodegenerative diseases that affect memory, such as Alzheimer’s disease.

About 25 per cent of us will experience the effects of anxiety disorders at some point in our lives, with sometimes dire repercussions for friends, family and our own well-being. Yet little is known about the molecular mechanisms in the brain which contribute to stressinduced anxiety. Dr Pawlak was recently awarded a prestigious EU Marie Curie Excellence Grant amounting to €1.7m over four years, to investigate how fear and anxiety are formed in the brain. The project could lead to more efficient ways of treating stress-related conditions.

Fear memories are encoded as changes in neuronal connections called synapses, in a process known as plasticity. Dr Pawlak and his colleagues have recently shown that proteases (proteins that cut other proteins) play a critical role in this process and significantly contribute to fear and anxiety related to stress.

Dr Pawlak commented: “Understanding neural bases of stress, fear and anxiety is of immense importance to modern society. The most dramatic form, posttraumatic stress disorder (PTSD) is characterised by cognitive impairment, depression, fear, anxiety, and may eventually lead to suicide.”

Head of Department, Dr Blair Grubb said, “These new research projects are only a sample of the active research programmes that are under way within the department. Well funded programmes studying aspects of cerebral palsy, deafness, pain, and movement control are also part of our overall research effort. This is a hugely exciting time for us.”

Source: By University Of Leicester

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