Cross-Disciplinary Award

Principal Investigator: Dr Matthias Eberl
School of Medicine

People whose kidneys stop working depend on therapies that replace some of the functions of the kidney. In the absence of sufficient donor organs for transplantation, such patients can only survive with the help of blood dialysis. In this form of treatment, the patient's blood flows through a filtering machine that removes toxic waste products from the body, and the cleaned blood is put back into the patient.

The presence of a permanent line for continuous access to blood over months or years poses a constant risk of infection for these patients, because microbes can enter the bloodstream via these lines. However, there is no quick diagnostic test available that will confirm a blood infection at the bedside. Patients with high temperature and suspected infections are therefore treated immediately with strong antibiotics "just in case" (because not treating them would be even riskier), which may at times be inappropriate and unnecessary.

Our project aims to develop novel tests based on the patient's immune system that can confirm the presence of an infection and identify the cause on the first day of feeling unwell, and thus make sure that the right treatment is given to the right patient, without delay.

Principal Investigator: Dr Timothy Bowen
School of Medicine

Around one in twelve of the global population suffers from diabetes, 40% of whom will develop diabetic kidney disease (DKD), a major cause of disability and premature death. Clinical interventions to delay DKD progression are challenging, and existing diagnostic tests for DKD are limited and may be invasive (e.g. require blood samples). We have shown that the urinary concentrations of three kinds of a recently-discovered family of molecules called microRNAs change in the urine during DKD. We aim to develop a microRNAdetecting sensor for a non-invasive urine test to allow: i) early DKD diagnosis and ii) prediction of disease progression over time.

Our present test consists of a dipstick sensor that is dipped into the urine sample. MicroRNA molecules attach to the surface of the sensor and their concentrations are detected electrically. However, protein molecules found in urine also stick to the sensor and interfere with accurate microRNA detection.

In this project, we will optimise sensor construction to achieve accurate detection of urinary microRNA targets by coating the sensors to prevent protein sticking. Once this key step has been achieved, our future studies will aim to simplify the test and make it suitable for use in the doctor’s surgery.

Principal Investigator: Dr Selinda Orr
School of Medicine

The incidence of inflammatory bowel disease (IBD) has increased in recent decades. Links have been found between IBD/colitis development, the presence of specific fungi in the gut and mutations in the genes/proteins that control fungal growth. Patients with IBD also have an increased risk of developing colon cancer. We believe that failure to control fungal levels in the gut may promote development or severity of IBD/colitis. As there are multiple genes/proteins that potentially work together to clear fungi from our bodies, we are asking the following questions:

• How do these genes/proteins work together to limit development or severity of colitis?
• Do specific fungi in the gut affect our risk for developing colitis?

We aim to gain a better understanding of how our immune system controls fungal levels and how this affects our risk of developing IBD/colitis. This will enable us to identify potential targets for developing new treatments for this debilitating disease.

Principal Investigator: Dr Jennifer Davies
School of Healthcare Sciences

Knee osteoarthritis is a common cause of disability and pain. There is no cure for Knee osteoarthritis, so it is important that we identify treatments that improve quality of life and slow progression of the disease.

During walking, people with Knee osteoarthritis have greater activity of the thigh and calf muscles than people without Knee osteoarthritis. This persists despite physiotherapy and has been associated with further joint deterioration. However, it is difficult to develop treatments because the cause of the increased muscle activity is not known.

To identify the cause we need to look at how the brain sends signals down the nerves in the spinal cord to the muscles. This requires experts in the brain, the spinal cord, and muscles, alongside physiotherapists with expertise in Knee osteoarthritis. This project brings together these people for the first time at Cardiff University to examine how the activity of the thigh and calf muscles is controlled in healthy individuals. The results will show that we are one of the few places in the world that is able to study this, and will allow us to go on to study cause of increased muscle activity during walking in people with Knee osteoarthritis.

Principal Investigator: Dr Jiaxiang Zhang
School of Psychology

Current drug therapies fail to control seizures in 30% of people suffering from epilepsy. However, there is yet a big gap between our theoretical knowledge of seizure generation and what is happening in the brain cells of patients. To address the urgent need of new effective epilepsy treatments, we need to understand how abnormal brain activity leads to seizures in humans. This project will take a cross-disciplinary approach, using mathematical and computational methods.

We will study data from a large group of 125 patients with epilepsy. During epilepsy surgery evaluation, several electrodes have been implanted deep in patients’ brain, and brain activity has been recorded before and during seizure. We will first examine how seizures arise from small brain regions, using mathematical models of neural networks that describe the changes of brain cells and their connections over time. Next, we will use the parameters of the models to simulate brain activity, and validate our method by comparing simulations with the real patients’ data. Our novel analysis on such a large group of patients will lead on to new therapeutic and surgical strategies for controlling seizures and eventually enhance the quality of life of epileptic patients.

Principal Investigator: Professor Eshwar Mahenthiralingam
School of Biosciences

Antibiotics have saved millions of lives since their introduction in the 1940s. They are drugs which form the foundation of modern medicine, without which multiple procedures such as surgical operations and cancer therapy could not take place. The emergence of widespread antibiotic resistant bacteria and severe lack of new antibiotics to treat them are recognised as global health threats that require urgent solutions.

Modern biological and chemical research can enable the rapid identification of new antibiotics if researchers work together and harness their strengths in these very different research fields. We have assembled researchers that are specialists in a new biological source of antibiotics, known as Burkholderia bacteria, and teamed them up with expert chemists who can use the latest analytical instruments to identify the new antibiotic molecules they produce.

We will identify the molecular structure of a new Burkholderia antibiotic that kills the superbug methicillin-resistant Staphylococcusaureus (MRSA). To bring this antibiotic closer to clinical use, we need to purify it in large amounts, determine its chemical structure, legally protect our discovery to allow commercial development, and finally understand if it is safe for use in humans.

Principal Investigator: Dr Oliver Castell 
School of Pharmacy and Pharmaceutical Sciences

Scientists are developing new drugs to treat many different diseases. One challenge though is how to get these drugs to where they are needed C inside the cells of your body.

We are investigating how nature has solved this problem. We hope to understand how specialist molecules move things across the barrier that is the cell membrane. If we can understand this process, we believe we can use the same approach to deliver promising new drugs too.

New microscopes have enabled us to see individual molecules one at a time. This allows us to understand how the cells that make up our bodies function at a new level of detail. We do this by tracking the work of individual molecules, or proteins, each a million times smaller than a pinhead. By watching these molecules we can glimpse into the world of the cell with detail not previously thought possible.

The molecules we are studying form tiny tunnels through the barrier of the cell membrane. These tunnels have inbuilt gatekeepers, only allowing the passage of special proteins and the cargo they carry. By watching exactly how these proteins work together we will learn how the tunnel works. We can then set about building a similar tunnel to transport drugs into otherwise impossible to reach locations… exactly where needed to treat disease!

Principal Investigator: Dr Jennifer Wymant
School of Pharmacy and Pharmaceutical Sciences

Breast cancer is responsible for >10,000 deaths yearly in the UK. New treatments are needed to reduce this significant burden on patients, families and society. A key research incentive is designing personalised approaches that combine diagnostic and therapeutic functions in one agent: “theranostics”.

Antibodies are natural immune system components that selectively bind to particular molecules. Their usefulness in cancer-targeting is well documented e.g. trastuzumab/Herceptin®, is used to treat breast cancer patients with high levels of the antibody’s target on their tumour cell surface. This is a cancer-promoting protein called HER2. We have identified a mechanism whereby trastuzumab/HER2 can be driven inside breast cancer cells via a natural process: endocytosis. We will exploit this to manufacture novel superparamagnetic-iron-oxide-nanoparticles (SPIONs) that are coated with trastuzumab and labelled for imaging. These new SPIONS will be tested for their ability to target HER2+ breast cancer cells: we will monitor how they are taken inside the cells, where they then go and how this affects HER2.

Principle Investigator: Professor Aled Clayton
School of Medicine

Cancer cells generate small fat-bubbles, which are like miniature cancer cells. These “Extracellular Vesicles (EVs)” are known to assist the growth and spread of disease, by finding their way into the bloodstream, and acting as lone-distance messengers. Whilst this process is unwanted, it presents researchers with an exciting opportunity. Perhaps EVs can be isolated from cancer patient’s blood, and analysed, to provide vital information about the presence and the status of cancer without needing an operation to retrieve a biopsy specimen. Indeed, measuring EVs during cancer treatment could also provide information about treatment success or failure.

Current methods for capturing EVs from blood involve multi-step laboratory procedures that are ineffective. They also fail to consider subtle sub-types of EVs, where some vesicles are likely more important in disease than others. We urgently need to make this easier, more efficient and more automated. We will generate a postage-stamp sized device that gently applies focused ultrasound waves across a fluid channel. Samples added to the channel will be flowed through the sound waves, resulting in the separation of EVs from other components. Successful fabrication and testing of the device will lead towards its application with clinical blood specimens, aiming towards a new scheme for the diagnosis and monitoring of patients with cancer.

Principle Investigator: Dr David Jamieson
School of Psychology

Enzymes are specialised proteins which carry out all of the chemical reactions that take place in your body. Understanding how these enzymes work is vital to developing new medicines that can treat more diseases with fewer side effects. Typically gaining this understanding requires specialist chemicals unique to a particular enzyme and lots of information to be pieced together from a range of different techniques. This can be expensive and time consuming, increasing the cost of drug development.

New technologies are required which will allow enzymes to be investigated quickly and without special chemicals. Towards this aim we have assembled a group of scientists with expertise in protein engineering, synthetic materials and microscopy. Together we will develop a new nano-tool 100,000 time smaller than a human hair that will be attached to individual enzymes and used alongside a specialist microscope to measure the reactions they are carrying out in real time. The resulting technology from these experiments will be a generic tool, not requiring special chemicals that can be used to measure many different enzymes as well as a wide variety of other biological molecules. The understanding this tool provides should enable the design of better medicines and treatments for diseases.

Principal Investigator: Dr Matthias Eberl
School of Medicine

Cerebrospinal fluid (CSF) is the clear and colourless fluid that surrounds the brain and the spinal chord.  Conditions such as traumatic brain injury, stroke, meningitis (infection) and brain surgery often lead to a build up of fluid pressure in the brain, which can cause headaches, dizziness, swelling of the head, loss of brain functions and even death.  Treatment involves removal of excess fluid by insertion of a temporary or permanent drain to release pressure on the brain.

The presence of a drain over days or weeks, at times forever, poses a risk of life-threatening infection for these patients, because microbes can enter the CSF via the drains.  However, there is no quick diagnostic test available that will confirm a CSF infection.

This project aims to lay the scientific foundation for the development of novel tests for brain infections based on the patient's own immune system.  Ideally, such tests will be able to identify on the first day of feeling unwell whether there is an infection, and thus make sure that the right treatment is given to the right patient, without delay.

Principal Investigator: Dr Michaela Serpi
School of Pharmacy and Pharmaceutical Sciences

There is a rapid global emergence of antimicrobial resistance (AMR), which has led to the failure of antibiotics to treat common infections. Without new antibiotics by 2050 it is estimated that AMR will cause 10,000,000 deaths and an associated $1 trillion global healthcare cost. Gram-positive bacterial strains of Staphylococcus aureus (eg MRSA), cause a significant number of life-threatening hospital and community-acquired infections. These bacteria also produce sticky growth forms called biofilms on medical devices such as catheters, which are highly resistant to clearance by antibiotics and the body’s natural defenses. Biofilms cause over 65% of recurrent and difficult to treat hospital-acquired infections. Consequently, S. aureus is designated by the WHO as a high priority pathogen for development of new antibiotics.

With an increasing number of vulnerable people in society (eg patients with cancer, receiving organ transplants and those requiring implanted medical devices), it is now imperative to discover new drugs effective against organisms such as S. aureus.  In this project, we will inhibit antibiotic resistant S. aureus by exploiting two promising and novel classes of antimicrobials. We will combine our expertise in pharmacology, synthesis, microbiology and the physical sciences to enhance the ability of the agents to kill bacteria and prevent biofilms formation.

Principal Investigator: Dr Helen Waller-Evans
School of Biosciences

Autophagy is the Greek word for “self-eating” and in a cellular context is used to describe how the cell breaks down and recycles its own machinery when this has become defective through wear and tear. Defects in autophagy lead to the accumulation of defective cellular machines (proteins) and compartments (organelles), which likely causes brain cell death in diseases like Alzheimer’s, and have been observed in Huntington’s disease. We use chemically-developed coloured tags that stick to autophagy machinery to study this process in cells. However, no commercially available chemical tag exists that emits red fluorescent light.

Our colleague Simon Pope has developed such a tag, called AQ2, which we have characterised as a specific chemical tag of autophagy machinery, and which is the subject of an upcoming publication. Several drugs are coloured and can emit light, mostly ultra-violet or blue, which interferes with drug screening using commercial autophagy tags. AQ2 could circumvent these issues since, unlike other tags, it emits non-interfering red light. The aim of this application is to test the utilisation of this new autophagy tag as a drug screening tool to both identify new potential therapies for Huntington’s and potentially commercialise this new technology developed at Cardiff University.

Principal Investigator: Dr Bevan Cumbes
School of Pharmacy and Pharmaceutical Sciences

Fluorescence microscopy has revolutionised our understanding of biology, enabling advances in our understanding of human health and disease. More recently single-molecule imaging has enabled unprecedented insight allowing us to visualise interactions of individual components of cells, culminating in the 2014 Nobel Prize in Chemistry.

In the Castell lab we use two such techniques to understand biological problems. Currently we use one technique to look at the cell surface and another to look deeper into the cell. In this project we will develop a way of combining the two, allowing us to look at different levels in the cell at the same time, with single-molecule resolution.

This advance in capability will enable us to tackle a wide range of new collaborative projects, for example: tracking the transport of molecules in the cell towards or from the membrane in drug delivery, cancer, neurodegenerative or heart diseases, or when bacteria share antibiotic resistance genes. This will improve understanding of these processes, leading to improved or novel treatments.