The group focuses on the following themes.
Rheumatoid arthritis and osteoarthritis are two of the most common forms of arthritis. Rheumatoid arthritis is a chronic inflammatory disorder whereas inflammation in osteoarthritis tends to be associated mainly with its later stages. Both are associated with loss of articular cartilage producing joints which are painful on movement.
Intervertebral disc degeneration
Lower back pain is a major health problem affecting approximately 80% of the population at some time in their lives.
Intervertebral disc degeneration has been implicated in approximately 40% of cases of low back pain and as such, is a promising therapeutic target. However, the current therapies are purely symptomatic or involve surgery, which does not address the initial causes of low back pain.
Our studies investigate the pathogenesis of intervertebral disc degeneration, with the aim of developing new therapeutic approaches targeted at the abnormal cell biology which results in such degeneration. Particular interests include the role of cytokines and chemokines, and targeted therapies to intracellular signaling molecules, cannabinoids and the use of stem cells for regeneration approaches.
Together with researchers in the Materials and Engineering Research Institute, Prof Le Maitre is working to develop a hydrogel delivery system for biological factors and mesenchymal stem cells to inhibit degeneration and induce regeneration.
Studies are led by Prof Christine Le Maitre.
Neurogenetic disease is caused by a defect or mutation in one or more genes which affects the nervous system. Collectively neurogenetic diseases affect around 1 in 1,100 patients in Northern England. Expanded genetic testing for these diseases results in the identification of novel DNA variants of uncertain significance (VUS) which do not lead to a clear diagnosis.
Our research looks at how we can functionally interpret DNA VUS. One approach that we use is to develop cell-based assays which can be carried out on patient samples. A second approach is to develop in silico or computer-based analysis of DNA variants. In silico analysis is used in clinical diagnosis as testing laboratories do not have the facilities to carry out experimental assays.
Both projects study the structure and activity of a protein complex called eIF2B. This complex is central to the cell response to stress which is altered in different neurogenetic diseases.
The final aim of our studies would be to create a bioinformatic pipeline which can be used to interpret the effect of novel variants on the eIF2B protein complex to improve patient diagnosis. This research may also identify therapeutic treatments for patients with rare disease.
Integrated Stress Response and disease
Cells in our bodies are constantly exposed to a range of stressful environments. To survive cells activate stress-responsive signalling pathways such as the ‘integrated stress response’ (ISR) which allows them to conserve energy and decide whether to recover from the stress or induce apoptosis and die. This makes the ISR critical for maintaining cellular homeostasis.
While the ISR is critical for maintaining cell function, such responses can also play roles in establishing dysfunctional states associated with prolonged stress exposure and the development of disease. A deregulated ISR is considered a major pathogenic mechanism in diseases ranging from cancer to neurodegeneration and more recently has even been associated with the cognitive decline associated with normal aging and cognitive impairment in Down syndrome.
The critical signaling event in the ISR is the phosphorylation of eukaryotic translation initiation factor, eIF2α, by one of four eIF2α kinases. eIF2 phosphorylation controls protein synthesis via inhibiting the activity of a partner complex, eIF2B. Using advanced biochemical and cell biology techniques, research in the Campbell and Allen lab groups is focused around understanding the molecular mechanisms controlling the regulation of eIF2/eIF2B during the ISR. In particular, they are interested in understanding how specific cellular localisation patterns of eIF2 and eIF2B play a functional role in controlling the ISR.
We are also interested in understanding whether the localisation of eIF2B in cells is important in the pathomechanism of other diseases which deregulate the ISR, in particular a rare childhood neurodegenerative disease, leukoencephalopathy with vanishing white matter (VWM) which is caused by mutations in eIF2B.
Studies are led Dr Elizabeth Allen in collaboration with Dr Susan Campbell and Dr Simon Turega together with other researchers in the Industry and Innovation Research Institute.
Multiple sclerosis (MS) is the most common disabling neurological condition among young adults, affecting around 85,000 people in the UK alone. MS is an autoimmune disorder which arises as result of the body's own immune system attacking the myelin sheath, a protective lipid rich membrane that surrounds the nerve fibres of the central nervous system. Damage to myelin interferes with the progress of messages between the brain and other parts of the body, causing the symptoms associated with MS.
Our research has a particular focus on the role of chemokines and the metalloproteinase family of enzymes in disease pathogenesis, in particular the enzyme ADAM17. Post-translational modification of arginine residues in a process called citrullination is also being assessed in people with MS, and in conjunction with neurology consultants at the Sheffield Teaching Hospitals NHS Foundation Trust. We are investigating the role this may play in autoantibody production in MS. It is hoped that this research will lead to the development of new therapeutics targeting inflammatory mediators.
Studies are led by Professor Nicola Woodroofe.
Schizophrenia is a severe brain disease that interferes with normal brain and mental function, and can trigger a range of symptoms including hallucinations, delusions and paranoia. Without treatment, the condition affects the sufferer's ability to think clearly, manage emotions and interact socially. Although there are a number of theories, the exact cause of the disease has not been determined and continues to be the focus of much research.
Genetic influences on the risk of antipsychotic-induced weight gain.
Over 1% of the general population will be prescribed antipsychotic drugs at some point in their lives. These drugs alleviate the symptoms of conditions such as schizophrenia in most patients, with the efficacy varying from patient to patient. Common side effects of these drugs include weight gain, this also varies between patients, with a significant genetic effect underlying the extent of the risk. Identifying the patients at highest genetic risk is important as weight gain is commonly cited as a reason for a lack of compliance by patients in taking their prescribed drugs. We are carrying out research to identify genetic variants which are associated with weight gain; it may be possible at the start of treatment to identify those people who would benefit from targeted additional support, or to optimise the choice of drug prescribed, increasing the likelihood of sustaining a healthy weight whist benefiting from the alleviation of their symptoms.
Studies are led by Dr Caroline Dalton in collaboration with Professor Gavin Reynolds.
Whether someone has a disease is usually affected by the details of their genome. We measure genomes by the order of bases in the DNA. The first version of a human genome was produced by the Human Genome Project and is called the reference genome; it is over 3,000 million bases long. In the past decade, obtaining the genomes of thousands of people has become possible using next generation sequencing. The results show that a person's genome is usually different from the reference at millions of places. Each difference from the reference is known as a variant. For some diseases, we know that particular variants in one or a few genes cause the condition. But for many other diseases, we haven't discovered which variants are detrimental.
Studies are led by Dr Lucy Crooks. Her primary interest is understanding the biological processes that are disrupted in schizophrenia. She was in the neurodevelopmental team of the UK10K project.
One area of Dr Crooks’ research is developing methods to identify variants that contribute to a disease from the data of a group of patients, under the assumptions that the variants can be in different genes and several variants may be necessary to produce the pathology. A second area of her research is determining an effective way to quality filter variants for datasets of a small number of individuals. Dr Crooks is also investigating changes in which transcripts of genes are expressed in different areas of the brain from RNA-seq data. Dr Crooks has a collaboration with Dr Rachid Tazi-Ahnini from The University of Sheffield to explore genomic variation in the Moroccan population. African populations are particularly important for measuring variants in healthy individuals because this is where genetic diversity is highest.
Temporal lobe epilepsy (TLE) is one of the most prominent forms of epilepsy in adults and is associated with hippocampal sclerosis. It's accompanied by a range of symptoms including temporary confusion, staring spells and uncontrollable jerking movements of the arms and legs.
Unfortunately, epilepsy still holds a certain stigma and if not treated properly can disrupt daily life. Some of the patients affected do not respond to drug treatments, despite numerous studies having been conducted to understand the reason for this. As such, there is still a great need for further research into the causes and pathogenesis of epilepsy.
Research in this area is led by Dr Alessandra Princivalle.
There are about 60 different types of muscular dystrophy and related neuromuscular conditions, all characterised by progressive muscle wasting or nerve deterioration. This can cause a loss of muscle strength and shortened life expectancy. The great majority are inherited conditions and have a genetic basis. Although there are presently no cures, gene therapy and cell therapy trials have been carried out, for Duchenne muscular dystrophy in particular.
Our research focuses on Duchenne, and on and myotonic dystrophies – associated with DNA expansions in the defective genotype. By examining gene expression patterns, it’s hoped that an understanding of the biochemical and cellular bases underlying the diverse genetic phenotypes can be developed.
Studies in this area are led by Professor Peter Strong.
Reproduction and infertility
The role of the endometrium is to accept the implanting embryo during impregnation. Endometrial dysfunction is associated with reproductive failure and in particular infertility and recurrent miscarriage. The endometrium undergoes cyclical changes and is controlled systemically by steroid hormones and locally by cytokines, growth factors and adhesion molecules.
Working with Professor T C Li of the Jessop Hospital in Sheffield, Prof Susan Laird has an ongoing interest in the local control of endometrial cell function and the way in which these local control mechanisms may differ in the endometrium of women with infertility and recurrent miscarriage. Areas of particular interest are expression of cytokines such as LIF and IL11 and chemokines such as CXCL12 and CXCL16 in endometrial cells and their effects on endometrial cell function. We are also interested in the role of endometrial natural killer cells in recurrent miscarriage and infertility.
These studies are led by Prof Susan Laird and Dr Adrian Hall.