Consolidator Award

Principal Investigator: Ismail Taban
School of Pharmacy and Pharmaceutical Sciences

Progression to metastatic disease is usually a devastating event for most cancer patients. It is estimated that around 90% of cancer deaths are attributable to poorly treated tumour metastasis, where there are no truly effective drugs in the clinic. Using computer aided design, new drug candidates have been generated in Cardiff to inhibit the action of a tumour metastasis associated protein known as Bcl3. Pre-clinical drug development studies are encouraging, with one such drug now showing promise as a therapy. For this aspiration to be realised, we need to understand the molecular basis of action by determining: (i) how well the drugs bind to Bcl3 through detailed biophysical analysis; and (ii) the atomic resolution details of the drug-protein interaction.

Recombinant Bcl3 protein will be generated, which in conjunction with the drug candidates, will allow us to undertake our molecular analysis. Our experimentally derived data will then be compared to predictions made in the computer modelling phase and existing cell biology data to confirm the drug works as expected, and in turn help us design new and better drugs that inhibit Bcl3.

Principal Investigator: Rhiannon Griffiths
School of Dentistry

Autoimmune diseases occur when an immune response is generated towards normal healthy tissues and organs. My research investigates a protein (transglutaminase 2 (TG2)) that has critical functions in tissue repair, but can also function abnormally and trigger an immune defence mechanism that attacks the body itself, resulting in disease. For example, in certain forms of arthritis immune cells attack joint tissues, causing inflammation and pain. TG2 has been shown to change the proteins that make up cartilage, causing the immune system to respond to this alteration and destroy the cartilage. In Coeliac disease (CD), TG2 activity changes ingested wheat proteins, causing an immune response that results in destruction of intestinal tissue.

This project will investigate exactly how TG2 influences the immune response, by studying its ability to cause immune activation. Understanding this mechanism will identify new approaches for drug intervention, which would prevent TG2 from acting in the locations/ during events where it can cause an abnormal immune response. Assessing this process in patients could also be used for diagnosis, for example of different types of arthritis. This would help advise the best type of therapy for individual patients, to ensure the best possible outcome.

Principal Investigator: Mateusz Legut
School of Medicine

Cancer immunotherapy uses immune cells called T-cells to eradicate cancer and was awarded Breakthrough of the Year 2013 by Science magazine. Cancer immunotherapy is already the first line of treatment for some cancers in the USA. Classically, this approach attacks cancer through molecules on the cancer cell surface called HLA. These HLA vary widely throughout the population as demonstrated by the difficulty in finding an organ donor match. This means that specific T-cells, or their HLA-recognizing molecule the T-cell receptor, can only ever be used in a minority of patients.

I have discovered new types of T-cell that can kill many different types of cancer without the requirement for HLA - but the identity of molecular targets "seen" by these cells is unknown. In this project I will use an unbiased approach which removes every gene in human genome one by one, to identify genes encoding new molecular targets recognized by HLA-independent, cancer-killing cells. These cells and their cancer-associated targets offer opportunities for pan-population, pan-cancer immunotherapies that I believe will revolutionize the way that we treat cancer in the future.

Principal Investigator: Divesh Baxani
School of Pharmacy and Pharmaceutical Sciences

Biological cells are tiny complex machines which come together in networks to form all the organs and tissues of our bodies. These machines rely on the ability to compartmentalise different chemical processes and communicate with each other using chemical languages. By replicating the way in which cells, tissues and organs work, we are able to tap into the wisdom of nature to make new kinds of sensing materials and models for scientists to test, as well as gaining insight into biology from a new perspective.

Using our unique engineering approach we will make individual model cells containing multiple compartments which are wrapped in the same barrier material that real cells use. Within these compartments, we will include molecules which can react with one another to make light, which we can easily measure, together with proteins that allow them to make their own energy, as cells do. We will assemble these individual units into artificial tissues that we can use as a model to understand biology. This model offers a new perspective which can be used by scientists to test different chemicals and drugs, to separate and study different biological functions, and make new devices inspired by biology such as light-emitting displays.

Principle Investigator: William Hill
School of Biosciences

Whether cancer has spread in a patient is often the defining factor in patient outcome. We now know breast cancer cells can spread around the body long before a tumour can be detected, but it is still unclear how these cells breakaway to invade other organs. Cancer starts with one cell going awry but it is surrounded by normal cells. We have found in the pancreas that normal cells recognise abnormal cancer cells and repel them out of the tissue for protection. However, this process could be accidentally helping the cancer cells spread to other organs.

This project will study in the breast whether normal cells influence breast cancer cells in a similar way and if this could be inadvertently helping the cancer spread around the body. By watching these interactions as they occur under a microscope and studying the cells forced out we can better understand how normal cells may promote the spread of breast cancer. This could lead to new targets to slow or even stop the spread of breast cancer throughout the body, improving the chance of survival for people living with this disease.

Principle Investigator: Daniel Morse
School of Biosciences

Bacteria and fungi can grow together in micro-communities known as biofilms, and within the human mouth hundreds of different species can co-exist without negative effects toward us. Sometimes, conditions in the mouth may change and allow the growth of undesirable microbes, resulting in infection. Denture-associated stomatitis is one such common infection affecting denture-wearers, and is caused by a fungus; Candida albicans. We have previously shown that if C. albicans and a range of oral bacteria are grown together in biofilms in the laboratory, the way that C. albicans behaves changes to a more infectious state, so we know that bacteria can influence the way other microorganisms behave, but how that happens is not clear.

This project will focus on identifying how this occurs, using specifically-selected bacteria from the mouth. The project will also use C. albicans taken from patients with and without the infection to see whether there are differences in how the fungi behave from patients with different severity of the infection. We will also use naturally-occurring probiotic bacteria to see if we can manage how the fungus behaves to stop the infection before it happens, and so reducing the need to use antimicrobials to treat the infection.

Principle Investigator: Naledi Formosa
School of Dentistry

Osteoarthritis is a degenerative disease of the joints which causes damage to the cartilage that lines the joint, and the underlying supporting bone. The damage and ultimate loss of cartilage results in pain, stiffness, and reduced function for patients. As more than one third of the population will ultimately be affected, there is an urgent need to develop new drugs for intervention. This depends on having adequate systems available to test potential drugs for safety and effectiveness before giving them to patients. Currently, the model systems available to researchers are animal based which makes them ethically problematic besides typically failing to accurately predict mechanisms of human disease.

Recent advances in the way cells can be triggered to form bone outside the body (my PhD), as well as cartilage (Cardiff laboratory), have made it possible to generate tissues in a culture dish. In this project, I will unite these advances with state of the art engineering to generate miniaturized human cartilage (Objective 1) and bone (Objective 2) tissues in an interconnected system to simulate a joint (Objective 3). This new joint tissue model will more faithfully replicate the human disease processes, and significantly shorten the time period needed to evaluate candidate drugs.

Principal Investigator: Katie Lewis
School of Medicine

Bipolar disorder (BD) is an illness where people experience episodes of very high or low mood. These episodes can be lethal; people with BD are up to 30 times more likely to die from suicide compared to the general population. Most people with BD repeatedly experience these episodes, which impair their functioning at home, in work or socially. It is therefore important to identify early warning signs so that interventions can prevent episodes.

Disturbed sleep in people with BD could be an early warning sign of an impending mood episode. However, existing research has produced equivocal results. To answer this question we need to study large samples of people over longer time periods and use advanced statistical techniques to analyse these data sets.

This project will use data from 1,118 people with BD who have used an online mood monitoring system to track their sleep and mood for up to three years. I will combine genetic data with advanced statistical methods to determine:

• whether sleep problems predict subsequent mood episodes
• which people with BD are more likely to become unwell following disturbed sleep.

This project will advance research on the causes of BD and inform future interventions.

Principal Investigator: Alessendra Crusco
School of Pharmacy and Pharmaceutical Sciences

Schistosomiasis is a neglected tropical infectious disease caused by parasitic flatworms (blood flukes), the second most socioeconomically devastating disease worldwide after malaria. Affecting over 200 million people worldwide and causing around 200,000 deaths every year, the disease is spread by contact with water contaminated with parasites from infected freshwater snails, and it is characterised by abdominal pain, diarrhoea and bloody stool/urine. Long-term infection can lead to liver damage, kidney failure, infertility, bladder cancer, poor growth and learning difficulties in children.

Control measures include snail elimination and treatment with the main anti-schistosomal approved drug, praziquantel (PZQ), whose use as single therapy has led to parasite insensitivity/resistance. Only few alternative drugs are in development, but none have been tested clinically. Not offering an attractive commercial opportunity for the private sector, research into much needed new therapies to help the poorest populations on the planet is severely neglected.

As an evolution of the work on the identification of new anti-schistosomal drugs I initiated during my doctoral studies, this project would allow me to further expand my expertise in this field with the optimisation of an early anthelmintic small-molecule hit, identified from a preliminary collaborative effort, into a potential new chemotherapy for schistosomiasis.

Principal Investigator: Carmine Varricchio
School of Pharmacy and Pharmaceutical Sciences

Cells of the human body contain structures called ‘mitochondria’ which convert the food we eat into energy. Approximately 1 in 5,000 of the UK population are affected by diseases that arise when these mitochondria malfunction. In particular, mitochondrial diseases of the eye lead to blindness. These diseases are currently incurable, hence there is a pressing need to identify novel therapies. A current cross-school collaboration between Optometry and Pharmacy has led to the discovery of a series of new and highly promising drug candidates that have the ability to restore the mitochondria energy in cells.

The current proposal concerns converting this discovery into a usable medicine. Drug delivery to the retina (back of the eye) is challenging and far from straightforward, so herein we plan to make a drug delivery system to release these new drug candidates right where they are needed. To do this, tiny structures called nanoparticles will be used to encapsulate and slowly release the drug to retina cells. By the end of the planned work, we will have identified a novel drug/delivery formulation ready for large scale testing required for use in the clinic.