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Disease mechanisms

Led by Professor Nicola Woodroofe, the Disease Mechanisms Research Group carries out research into the molecular basis of several disease states. The group focuses on the following five themes.

Cancer

Cancer is a genetic disease characterised by excessive cell proliferation, migration and invasion, which result in tumour development and its subsequent spreading to other tissues and organs. Phenotypic alterations in cell morphology and function are underlined by changes in gene/protein structure and expression. Expression of many other proteins is aberrant – either elevated or reduced. For example, expression of matrix metalloproteinases is increased, resulting in modifications in extracellular matrix. This facilitates release of cancer cells from the tumour and their spreading.

Many currently developed anti-cancer therapies exploit knowledge of the fundamental molecular and cellular mechanisms involved in tumour formation and progression, including changes in the function and expression of the crucial proteins.

Studies in this area are led by Dr Neil Cross, Prof Christine Le Maitre and Dr Nikki Jordan-Mahy

Role of cancer stem cells in tumour development

Recent evidence suggests that tumours comprise differentiated tumour cells (which have a limited life-span) and cancer stem cells/tumour initiating cells (which are undifferentiated cells with unlimited replicative ability and the ability to differentiate). The cancer stem cells hypothesis suggests that if cancer stem cells are selectively ablated, tumour growth will cease and eventually the tumour will regress. In this study we are investigating whether cancer stem cells are present in primary uveal melamona tissue and, if so, whether they can be selectively targeted by chemotherapeutic agents.

The study is based on our observations that 'primitive' tumourigenic sub-populations of cells with no cytogenetic aberrations are present in uveal melanoma tumours, in contrast to the majority of the cells within the tumour. These cytogenetically 'normal' tumour cells may represent cells at the earliest stage in tumour development and, as such, may represent the cancer stem cell population in uveal melanoma.

Related studies on prostate cancer are also addressing the cancer stem cell hypothesis. These studies are in collaboration with Dr Karen Sisley, University of Sheffield.

TMPRSS2 :ERG fusion gene in prostate cancer

The majority of prostate cancers have a recurrent translocation involving the Ets-related gene/ERG oncogene and the androgen-responsive promoter of the TMPRSS2 gene, resulting in androgen-driven ERG expression. Although androgen-driven oncogene expression should represent an Achilles' heel for prostate cancer, since primary treatment of prostate cancer is by androgen withdrawal, this is not the case. Using cell lines that express this fusion gene, studies are aimed at investigating how androgen withdrawal affects ERG expression, and how cancer cells ultimately bypass ERG silencing in the absence of androgens.

These studies are in collaboration with Dr Colby Eaton, Academic Unit of Urology, University of Sheffield.

Factors regulating the activity of the anti-tumour agent TRAIL

Recent studies have focused on how tumours evade apoptotic signals from Tumour Necrosis Factor (TNF) superfamily members, with particular emphasis on the potential anti-tumour agent TRAIL (TNF-Related Apoptosis Inducing Ligand), its receptors (Death Receptors 4 and 5) and decoy receptors (Decoy receptors 1 and 2, and OPG(Osteoprotegerin). Current studies are focusing on mechanisms of TRAIL resistance in cancer cells, and whether combinations of agents such as histone deactylase (HDAC) inhibitors, nuclear export inhibitors and proteasome inhibitors can reverse TRAIL resistance. In our recent studies, we have also demonstrated that nuclear export inhibitors in particular can potently enhance tumour cell sensitivity to TRAIL in a range of tumour cells.

Nutraceuticals in the prevention and treatment of cancer

We are currently researching a number of novel compounds derived from fruit and vegetables. This involves.investigating the biological effects on tumour and non-tumour cells of agents derived from carrots, pomegranates, rhubarb, beetroot, cabbage and broccoli. Specifically, we are interested in their potential to induce cell death and inhibit proliferation, and the molecular mechanisms of their actions. We have a particular interest in leukaemia, prostate cancer, gastrointestinal tract cancers and breast cancer.

Musculoskeletal disorders

Arthritis

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, Dr 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 with Dr Alison Cross and Dr Gail Haddock.

Neurological diseases

Multiple sclerosis

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

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.

Studies are led by Dr Caroline Dalton in collaboration with Professor Gavin Reynolds.

Epilepsy

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 routine. Some of the patients affected do not respond to drug treatments, despite a large number of 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.

Chronic diseases

Muscular dystrophy

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.

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