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RA5a: Structure,environment and staffing policy

We are committed to the integration of studies of basic mechanisms underlying human disease with translational research, patient-orientated clinical research, and a seamless transition to excellence in clinical practice. Six priority research themes have been supported since 1996: A) Immunity and Infection, B) Endocrine Basis for Disease, C) Genetic Susceptibility, D) Gastrointestinal Epithelial Biology, E) Cardiovascular Sciences and F) Clinical Trials and Gene Therapy. Integration of Departments of Medicine, Surgery, Anaesthesia and Intensive Care, Cardiovascular Medicine, Geriatric Medicine, Clinical Trials and Physiology into a single Division of Medical Sciences has facilitated this strategy. Each research theme comprises a vibrant mix of clinical and basic science research, underpinned by significant peer-reviewed funding, including Fellowships. This environment stimulates extensive scientific cross-talk between themes thereby enhancing scientific output for our given HEFCE resource. Close integration with local NHS Trusts has enabled the application of a strong laboratory research base to Clinical research, using the unique large patient resource (ca 5.5 million or 10% of the UK population) of diverse ethnic mix. Research opportunities have been greatly strengthened by funding awards for a Clinical Research Facility (Wellcome Trust Millennial Grant £3.24M), a £28M Institute for Biomedical Research (JIF/Wellcome Trust £18.7M), National NMR Centre (JIF £7M, JREI £1.34M), recently completed Cancer Institute (£5M) and Birmingham Clinical Trials Unit (NHS R&D £2.3M).

Research Themes

A IMMUNITY and INFECTION

Major advances have been made on the immune basis of clinical disease with an important emphasis on translational work. Closely interlinked programmes bring together clinical science specialties from hepatology, nephrology, rheumatology, respiratory medicine, ophthalmology, pathology and surgery.

Molecular mechanisms of chronic inflammation (liver disease, renal disease, vasculitis, rheumatoid arthritis). These diseases form the clinical focus of the MRC Centre for Immune Regulation in which Buckley, Savage and Adams are principal investigators. Important contributions to understanding the control of leukocyte recruitment have been made using in vitro models, including a flow-based adhesion assay developed by Nash. Adams reported the involvement of novel adhesion molecules (2 patents) in liver-specific lymphocyte recruitment and Buckley elucidated the mechanisms of action for other molecules including CD31. The microenvironment is instrumental in driving chronic inflammation; stromal cells and specific chemokines play a central role in the retention and survival of lymphocytes in the inflamed joint (Buckley with Salmon UoA1). New mechanisms of tissue damage have been proposed by Savage and Nash who showed that autoantibodies can trigger leucocyte activation and recruitment (with Wakelam UoA1) and by Adams, Hubscher and Afford (with Young UoA1) who reported that cooperative interactions between CD40 and Fas can amplify tissue damage and inflammation. These studies have been supported by MRC Senior Clinical Fellowship to Buckley, EC Framework V programme, BHF, ARC, Wellcome, and BBSRC project grants, with industrial support from Pfizer USA, Genetics Institute and Fujisawa. The translational element of this work is emphasized by forthcoming clinical studies using antibodies to VAP-1 to block lymphocyte recruitment to the liver in patients with inflammatory liver disease (with BioTie Therapeutics).

Infection and Inflammation. Stockley, He and Hill have elucidated the role of inflammation and bacterial colonisation in neutrophil-mediated connective tissue destruction in emphysema. Their work shows that airway colonisation is a potent stimulus for chronic inflammation and trials of anti-inflammatory therapy are ongoing. Stockley is Director of the UK registry of patients with alpha-1-antitrypsin deficiency (A1ATD) and a founder-member of the International A1ATD Registry which has allowed him to develop clinical trials of replacement therapy. He was recently recruited from Cambridge to work on the molecular biology of A1AT (funded by BLF). Adams discovered a role for particular chemokines in the inflammatory damage of chronic Hepatitis C virus (HCV) infection. Buckley and Curnow (with Salmon, Moss and Rickinson UoA1) have proposed a novel model to explain the dynamics and persistence of immune memory for chronic viral infections. Mutimer used sensitive assays including antigen-specific tetramers (with Moss UoA1) to report detailed dynamics of post-liver transplant infections with CMV and EBV. He also demonstrated the role of host and immune factors in driving viral mutation and drug resistance in hepatitis B (with Pillay UoA1). These studies are linked to large international trials of the treatment and monitoring of HCV, HBV and EBV in post-transplant patients. Knutton (Wellcome Trust programme grant) used high resolution imaging techniques to define how enteropathogenic and enterohaemorrhagic E. coli interact with intestinal epithelial cells (with Booth and Pallen – collaborator and newly appointed Chair of Microbial Genomics). They showed the involvement of a novel surface organelle of E. coli in protein translocation into epithelial cells, and the role of the type IV bundle-forming pilus and EspA-EspB interactions in bacterial adherence, aggregation and dispersal.

Immunopathogenesis and clinical assessment of autoimmune disease. Neuberger and Joplin are the first to demonstrate the presence of the autoantigen PDCE2 on bile ducts, the target cells in primary biliary cirrhosis. They defined the target antigen and immune interactions with epithelial cells and reported evidence for a transmissible agent in PBC using human cholangiocytes. With Kelly and Strain (UoA14) they described the development of distinct subsets of cholangiocytes from putative hepatic stem cells. Murray reported mechanisms of immune activation in intraocular inflammation and has recruited Curnow from Oxford to extend this work with Salmon (UoA1). In related studies Winer evaluated the immune basis of Guillain-Barre Syndrome. Cockwell, Howie, Adu and Savage demonstrated that autoantibody-mediated neutrophil activation in vasculitis is mediated via specific intracellular signals including integrin and FcRIIa activation (with Nash and Buckley) and G-protein stimulation of PI3-kinase and PKB (with Wakelam UoA1). This work has informed clinical trials funded by EC Biomed2 and the European Vasculitis Study Group. Bacon, Gordon and Adu instigated the development of international assessment indices for systemic connective tissue diseases (Systemic Lupus International Collaborating group, EC Vasculitis Collaborative Action Group) and the Birmingham Vasculitis activity score and damage index are used internationally. With Townend, Bacon used these tools to show that depressed endothelial responses reflect vascular damage which improves after aggressive therapy of systemic vasculitis. Southwood is an international leader in the development of classification systems for paediatric arthritis and Bowman (MRC Clinician Scientist) has developed clinical assessment tools for Sjogren’s syndrome (with Hobbs UoA2). Bowman reported T-cell responses to peptide epitopes of the human Ro/La protein in SLE and Sjogren’s. Young and Bacon showed that aberrant cell signalling leads to T-cell dysfunction in rheumatoid arthritis as a consequence of disordered protein kinase activity in response to TNF and T cell receptor signalling.

Transplantation Immunology. Candinas and Stroka have recently been appointed to continue research initiated at Harvard and University of Zurich on hypoxia-dependent genes in allograft rejection and in chronic inflammation where tissue hypoxia is critical in regulating leukocyte recruitment, activation and survival. Stroka defined the role of NFkB and survival genes in regulating endothelial cell activation and Candinas carried out seminal studies into the role of protective genes and ATP in endothelial activation. They have developed a transgenic mouse model to study the role of HIF-1 in hypoxic damage (Swiss Science Foundation). Afford demonstrated that hepatocyte loss in chronic liver rejection is amplified by a novel macrophage-driven mechanism of apoptosis. Savage, Cockwell, Howie, Hubscher and Adams demonstrated roles for particular chemokines and adhesion molecules in lymphocyte recruitment to human allografts. This work has major ramifications for the large multidisciplinary transplantation programme (Elias, Neuberger, McMaster) and the pathology of graft rejection (Hubscher, Howie). Hubscher helped develop the European and Banff scoring systems for allograft rejection. McMaster has pioneered innovative immunosuppressive regimens including the European study of tacrolimus and Elias and Neuberger are international authorities on selection, prognostic modelling and outcome in liver transplantation. The theme shares common interests and techniques with the Regional Bone Marrow Transplantation group (Moss, Craddock, UoA1).

B ENDOCRINE BASIS FOR DISEASE

This research theme has combined excellence in laboratory-based research, notably molecular endocrinology, patient-orientated clinical research and epidemiogical studies to investigate the underlying basis of several human diseases.

Enzymes and Hormone Action. Stewart, Hewison, Kilby, Kumar, and Sheppard have defined the critical role of pre-nuclear receptor metabolism of hormones in determining tissue-specific hormone action. This new concept in endocrine function has ramifications for the pathogenesis of common diseases such as obesity, hypertension and osteoporosis whilst offering development of potentially novel therapies.

Studies of 11b-hydroxysteroid dehydrogenase (11b-HSD) and corticosteroid hormone action are funded largely through the MRC (SCF to Stewart, project grants, 3 Clinical Training Fellows, ROPA and equipment). Using a combined laboratory and clinical approach, Stewart identified mutations in kidney 11b-HSD type 2 isozyme in patients with hypertension and is applying molecular genetics to evaluate this enzyme as a candidate gene in the development of ‘essential’ hypertension and nephropathy. With Kilby he showed this enzyme to be expressed in the feto-placental unit and reduced in pregnancies complicated by intrauterine growth retardation (IUGR); this may be a factor underpinning the ‘Barker hypothesis’ (collaboration with MacLeod, Hobbs, UoA2). Conversely, the type 1 11b-HSD enzyme activates cortisol from cortisone in adipose tissue, which facilitates glucocorticoid-induced adipocyte differentiation resulting in central obesity. The characterisation and regulation of 11b-HSD isozyme expression has been studied in human bone (Hewison) and ocular tissues (Murray) and its relevance to osteoporosis and glaucoma is being evaluated. Purification and structural analysis of 11b-HSD isozymes expressed in E.coli was achieved with White and Ride (UoA14)(J Biol Chem 2001) and specific inhibitors identified by high throughput screening technology for future therapeutic development (patents and collaboration with Pfizer, USA). In related studies the tissue-specific metabolism of androgens and oestrogens by aromatase and 17b-hydroxysteroid dehydrogenase in human adipose tissue, bone and colon has been characterised and may be important in explaining the sex-specific differences in fat distribution, osteoporosis and colon cancer (with Langman). Human vitamin D 1a-hydroxylase has been cloned and its expression detected for the first time in renal and extra-renal sites (Hewison, Stewart). The role of vitamin D metabolism in modulating the immune response during fetal development (BBSRC with Kilby) and in patients with metabolic bone disease (NKRF with Savage) is being defined. Franklyn, Kilby and Gittoes documented reduced levels of circulating thyroid hormones and expression of thyroid hormone receptors in the CNS and placentae of fetuses with IUGR, suggesting that altered thyroid hormone action may contribute to neurodevelopmental abnormalities. To test the hypothesis that T3 supply to thyroid receptors is also perturbed in this condition, the roles of specific iodothyronine deiodinases are being explored (MRC support).

Endocrine Cancer. Research has focussed on the aetiology of pituitary and thyroid tumours and the roles of hormones in malignancies such as leukaemias, breast and prostate cancer. Franklyn, Gittoes (MRC Career Development Award) and Sheppard defined expression of the pituitary tumour transforming oncogene (PTTG) in a large cohort of patients with pituitary tumours (Regional Pituitary Clinic). Adenoviral systems of gene delivery are now being used to study the relationship between PTTG and growth factor signalling in pituitary cells with Mautner and Young (UoA1). The observation that PTTG is involved in cell division has prompted analysis of its role in other tumours and normal fetal development – high levels of PTTG are found in fetal tisues with a clear ontogeny of expression (Kilby). Abnormal expression of thyroid and steroid hormone receptors and ‘pre-receptor’ enzymes has been demonstrated in human pituitary tumours. This research is enhanced by the appointment of Toogood (Clinical Lecturer) who recently cloned the ghrelin receptor (with Thorner, Charlottesville, USA). Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, stimulates GH secretion in vivo. Its role in human malignancy, including GH-secreting pituitary tumours, is being investigated (collaborators Stewart, Sheppard, MRC ROPA). Studies on thyroid cancer and goitre (Franklyn, Sheppard, Eggo, Mautner, Seymour and Logan UoA5) have shown over-expression of FGF and FGFR by thyroid follicular and endothelial cells in goitre (human and rodent) and thyroid cancer. Angiopoietins 1 and 2 and their receptor, Tie-2, were found to be over-expressed in thyroid follicular cells from human goitres. The targeted delivery of genes via adenoviral vectors to control tumour growth using the TSH receptor promoter is in progress (Wellcome Trust grant, MRC Training Fellowships). Novel hormonal approaches to differentiation therapy in acute myeloid leukaemia are being developed (Brown, Bunce (LRF Bennett Fellow), Hewison and Hughes). Two new targets, the nuclear receptor PPAR and an aldoketoreductase type steroid dehydrogenase, have been identified within primitive myeloid cells which when targeted with clofibrate and indomethacin render AML cells responsive to physiological differentiation signals. Translational studies have led to a phase II trial of indomethacin and all-trans retinoic acid as combined differentiation therapy in patients with myelodysplasia (Brown, Drayson with MacLennan UoA1). Differential display techniques have been used to identify genes associated with changes in vitamin D receptor (VDR) expression in haematopoietic cells and VDR transactivation is being analysed in leukaemic cells (LRF-funded). Studies on the role of vitamin D3 and its metabolites in cancer (Campbell (new Lecturer), Hewison, Stewart) have focused on inappropriate metabolism of vitamin D3 by the enzyme CYP24, recently identified as an oncogene in breast cancer. The antiproliferative effects of vitamin D3, but pro-differentiation effects of some of its metabolites, have been defined in human prostate and breast cancer. The role of receptor co-repressor proteins with histone deactylase (HDAC) activity, which act to normally maintain the unliganded receptor in a transcriptionally silent state, has been identified (with Turner UoA6).

A Reproductive Biology group (lead Barratt), formed by an innovative partnership between the Birmingham Women’s NHS Trust and University, is studying molecular interactions between human spermatozoa and egg, apoptotic mechanisms in human testis, and membrane progesterone receptor in human spermatozoa (with Stewart) and is developing expression arrays for identifying human genes involved in spermatogenesis. Collaboration with Publicover (UoA14) has established a highly competitive group analysing calcium channels and spermatozoa function. St John works on mitochondrial DNA in placental development and, with Shatten (Oregon), studies the role of paternal mitochondrial DNA in early embryo development in human and primate systems. Hughes identified the function of rodent and human zona proteins and their ZP domains.

Endocrine Databases. A computerised Thyroid Register with records on over 15000 patients has allowed analysis of long-term consequences of thyroid disease and its treatment, including mortality data (Franklyn, Sheppard). It provides an extensive DNA resource for studies on autoimmune and nodular thyroid disease, linking phenotype, genotype and outcome. The West Midlands Pituitary Register (Stewart, Sheppard, Wheatley) contains data on over 1500 patients with pituitary disease. Studies have defined premature mortality, predominantly from vascular disease as well as definition of specific risk factors (Lancet 357:425-31,2001). Novel therapies for patients with pituitary disease have been evaluated (support from NHS R&D, industry). Genomic DNA and tissue DNA banks are being established to extend studies on the molecular basis of pituitary tumorigenesis and provide a unique national resource for the wider scientific community. Information from these databases have set standards for clinical practice in areas such as thyroid cancer, thyroid-related atrial fibrillation and pituitary surgery and radiotherapy.

C GENETIC SUSCEPTIBILITY

The application of molecular genetics to malignancy, development, autoimmune disorders and Parkinson’s disease has defined the molecular basis for some of these conditions and led to the identification of novel disease susceptibility genes.

Cancer Genetics. Maher, Latif and Richards, funded by a CRC programme grant, have analysed the molecular basis for susceptibility to common cancers and key gatekeeper genes for non-familial cancers including lung, breast and kidney are being identified (with Macdonald). Their isolation of the von Hippel Lindau (VHL) tumour suppressor gene (TSG) provided a paradigm of how understanding of a rare familial condition can be applied to pathogenesis of non-familial cancers such as renal carcinoma. Current research focuses on isolation of further TSG’s implicated in familial and sporadic renal cell carcinoma, mechanisms of epigenetic VHL gene inactivation in tumours, and function of the VHL gene product, including its role in angiogenesis. Recent research identified a 3p21 TSG, RASSF1A, that is epigenetically silenced in many adult and paediatric malignancies. Grundy and McConville are pursuing research into the molecular pathology of paediatric cancers such as neuroblastoma, Wilm’s and brain tumours.

Developmental Genetics. This research programme identified a congenital heart disease gene at 3p25 gene (a small candidate region has been identified and the contribution of the gene to familial and sporadic septal defects is being analysed) and investigated genomic imprinting and human growth and development. The human imprinting disorder Beckwith-Wiedemann syndrome (BWS) provides a model for determining mechanisms and consequences of imprinting control and human and mouse molecular studies on BWS are in progress (Maher). Maher is a member of the MRC Cooperative Group on Imprinting and Growth coordinated by Ferguson-Smith (Cambridge). The multiethnic composition of the West Midlands population provides excellent opportunities for mapping and characterising autosomal recessive disorders. Clinical, epidemiological and molecular studies of recessive disorders in consanguineous families in the West Midlands were initiated by the late Sarah Wright/Bundey (with Farndon). These studies provided a basis for the UK Autozygosity Linkage Consortium (Maher, Trembath, Mueller and Woods) and National Autozygosity Mapping Resource (Wellcome Trust Biological Resources Initiative 2001-2006).

Diabetes Mellitus and Autoimmune Thyroid Disease. Barnett, Bain, Gough and Kumar had pivotal roles in establishing the BDA Warren 1 Repository of immortalised cell lines from Multiplex Families with Type 1 diabetes, cell lines from Type 1 diabetics who have survived >50 years (Golden Years Project), and a UK DNA resource from patients with diabetic nephropathy (MRC, Wellcome Trust, BDA, JDF, NHS R&D and Industry funding). The Warren clinical database has demonstrated a high degree of familial clustering of other autoimmune diseases. This is being used to focus genetic linkage studies with Todd (Cambridge) aimed at defining loci conferring susceptibility to the autoimmune process, and elucidation of structural requirements for natural HLA-DQ-mediated protection against type 1 diabetes. The largest world-wide collection of genomic DNA from index cases with autoimmune thyroid disease and family members has been established by Gough, Franklyn and Allahabadia (Wellcome Trust). A UK-wide collection of immortalised cell lines (European Collection of Cell Cultures; Wellcome Trust, JDF) will facilitate genomic searches for loci conferring susceptibility to autoimmune diseases. Immune response genes conferring susceptibility, including HLA and CTLA-4, have been identified; further loci identified by positional cloning will be evaluated in collaboration with functional immunologists in MRC Centre for Immune Regulation (Lane UoA1). Barrett has established a programme in childhood diabetes based on his seminal studies on the Wolfram syndrome (with Hattersley, Exeter) and genetic studies of hypothyroidism.

Parkinson’s Disease. Ramsden and Williams (with close links to Neurosciences, UoA5) are exploring the hypothesis that an individual’s genetically determined ability to metabolise xenobiotic compounds is a predisposing factor in Parkinson's disease. A case control study involving over 1000 patients has investigated the role of 14 loci in 8 genes, including catechol-O-methyltransferase (COMT) and heme oxygenase-1 (HO-1). Collaboration with Ho (Hong Kong University) has shown effects of oestrogens on COMT metabolism and dopamine on HO-1 expression in neuronal and glial cell lines.

D GASTROINTESTINAL EPITHELIAL BIOLOGY

The group has a major interest in defining factors that control normal epithelial cell function throughout the gastrointestinal tract and how this is disturbed in premalignant conditions such as Barrett’s oesophagus and in established malignancy. Success of a multidisciplinary approach is illustrated by MRC, Wellcome and RCS-funding of medical and surgical research fellows and CASE awards.

Jankowski works on the dysregulation of cadherins in conditions in which the epithelial integrity of the GI tract is compromised, notably Barrett’s epithelium and inflammatory bowel disease. He was the first to show that b-catenin translocation from the membrane to the nucleus, where it induces transcription factors (COX-2, cyclin D1 and c-myc), is an important signalling pathway in tumour progression. He is now focusing on the potential role of cytokines of the TNFa family and the growth factor TGFa (both over-expressed in Barrett’s) in this dysregulation process, using cell culture models and epithelial stem cells as well as fresh tissue. These signalling events and the effect of alterations of E and P cadherin expression are being examined on crypt bifurcation, which is a surrogate marker of stem cell division and hence clonal expansion. Collaborators include Young (UoA1), Adams and Maher (CRC, MRC and Wellcome Trust funding). Doe’s expertise in cytokine effects, oxidant-induced injury and mutation screening in inflammatory bowel disease and colorectal cancer has strengthened the group.

The progression of normal gastrointestinal epithelium to a malignant phenotype is being defined by Morton, Matthews and Chidgey. This group applied high resolution mapping techniques to two regions of deletion on short arm of chromosome 8 in prostate and squamous cell head and neck cancer (MRC). Studies are now focused on colorectal neoplasia (MRC, RCS Fellowship) and a novel tumour suppressor gene, frizzled related protein 1 (frp-1), has been identified and its genomic sequence characterised. Deletion of frp-1 is being investigated in a keratinocyte cell line model with Gallimore (UoA1). Loss of frp-1 results in reduced E-cadherin expression, disruption of desmosomal junctions and disordered intracellular beta catenin signalling (with Jankowski). The influence of this gene on COX-2 expression in early colorectal neoplasia is also being investigated (Wellcome Trust). Chidgey’s work on desmocolin II has enabled the development of a knock-out mouse; he is currently defining the gene’s promoter sequence (BBSRC; with Taylor UoA1 and Thomas UoA14). Morton helped establish an international polyp prevention study using novel COX-2 inhibitors for which Birmingham is the national centre (MSD). The clinical department was a centre for the national screening study of once-only flexible sigmoidoscopy (MRC/ICRF).

Singh and Langman defined the regulation of apoptosis in colonocytes by estrogen, protein kinase C, NSAIDs, PPARg activators and IGFs. They showed the key roles of the energy substrates butyrate, glucose and glutamine in regulating colonocyte growth and function. The enzyme rhodanese is responsible for detoxification of hydrogen sulphide in the colon and the effects of hydrogen sulphide on colonocyte energy metabolism and of rhodanese polymorphisms in patients with ulcerative colitis are being studied.

E CARDIOVASCULAR SCIENCES

The Cardiovascular group investigates the underlying basis for atherosclerosis, angiogenesis, thrombosis, hypertension and cardiac arrhythmias. The group shares many research methodologies with the neural control of cardiovascular function group in Neurosciences (UoA5). The new BHF Chair of Cardiovascular Medicine will expand collaborative opportunities and lead a multidisciplinary Cardiovascular Sciences initiative.

Endothelial cell biology and Angiogenesis. Nash and Rainger (BHF programme grant and Lectureship, BBSRC and Wellcome Trust) have developed a flow-based adhesion assay to study leukocyte interactions with the vessel wall during inflammation. Links between kinetics of integrin activation, cytoskeletal rearrangement, rigidification and motility in neutrophils have been reported (with Wakelam UoA1). Rainger has developed systems for co-culturing endothelial cells with macrophages and smooth muscle cells to investigate role of cell-cell interactions in the vessel wall in the development of atherosclerosis and vasculitis and this approach is now being extended to hepatocyte/endothelial co-cultures and stromal cell co-cultures (Buckley). The relative importance of ‘adhesive’ and chemotactic signals in regulating neutrophil migration and links between integrin receptors and the cytoskeleton are being explored with Hotchin, Machesky and Insall (UoA14). How disruption of ‘normal’ processes of adhesion and migration lead to occlusion and damage to vessels is being studied using in vitro and intravital systems to model inflammation and angiogenesis (Egginton). Ahmed and Whittle defined molecular mechanisms of angiogenesis, vascular disorders relating to women's health, and the role of second messenger gases in the pathophysiology of vessel development, function and protection (BHF programme grant, Wellcome Trust). The expression, function and inter-relationship between the two key angiogenic ligand-receptor systems (VEGF and angiopoietins) are being studied in placental and endothelial tissues. A molecular explanation for defective angiogenesis in the pathogenesis of intrauterine growth restriction has been provided. Studies on the role of VEGFR-1 in endothelium will have therapeutic implication for endothelial revascularisation following injury, atherosclerosis, diabetic retinopathy, and solid tumour growth. The early response genes regulated by VEGF receptors are being investigated using cDNA arrays to analyse endothelial cells exposed to receptor-selective neutralising antibodies. Egginton is defining the role of metalloproteinases in controlling different forms of capillary growth and examining the role of anti-angiogenic factors in modulating actions of pro-angiogenic cytokines and growth factors in muscle during increased activity. With Hudlicka (Emeritus Professor) and Brown (UoA69) he showed that flow shear stress and muscle stretch independently cause capillary angiogenesis which is related to muscle fibre type and size. He is investigating mechanisms of endothelial cell mechanotransduction responsible for angiogenic activity and the integrated pattern of gene expression during angiogenesis.

Cardiovascular function and arrhythmias. Studies on the use of site-specific cardiac pacing to control cardiac function and arrhythmias are supported by MRC and BHF (Gammage, Townend, Griffith, Bonser). These are facilitated by the large tertiary referral practice for cardiology at UHB Trust and recent extension and refurbishment of the cardiac autonomic physiology laboratories (BHF support). Specific achievements include functional benefits of alternative right ventricular pacing sites and potential to prevent and treat atrial fibrillation using a combination of novel pacing algorithms and new atrial and ventricular pacing sites. Clinical studies have revealed that atrial arrhythmias are largely responsible for increased vascular morbidity and mortality in patients with treated thyroid disease (with Sheppard, Franklyn). Studies of flow-mediated dilatation in the brachial artery have elucidated the role of hyperhomocysteinaemia as a cause of endothelial dysfunction, especially in renal failure (Wheeler); this technique has been extended to investigate endothelial function in SLE and necrotising vasculitis (Bacon, Gordon).

The Haemostasis, Thrombosis and Vascular Biology Unit (Beevers, Lip, Blann) is jointly funded by City Hospital NHS Trust and University. Principal clinical interests are ethnic differences in blood pressure, epidemiology of hypertension, atrial fibrillation (AF) and heart failure (with Kendall). The Unit has a major involvement in INTERSALT and INTERMAP, large international epidemiology studies evaluating the relationship between nutrients and blood pressure, and is a major centre for the ASCOT study, an international hypertension trial comparing new and old antihypertensive regimes. Collaborations are in place with UoA2 on two major projects: Screening for AF in the Elderly (NHS R&D) and Birmingham AF Treatment Assessment study (MRC) and in psychological aspects of cardiovascular disorders (UoA69). Bradbury (recently appointed Professor of Surgery) has expertise in surgical and endovascular management of lower limb ischaemia, arterial wall compliance and progression of arterial disease, and chronic venous insufficiency and ulceration. Recent awards (> £1M) include HTA multi-centre trial of cost-effectiveness of percutaneous transluminal angioplasty (principal applicant) and MRC Ulcer surgery trial (co-applicant). With Nash and Rainger, he is investigating the effects of exercise in patients with intermittent claudication on inflammatory humoral markers, coagulation, fibrinolysis and endothelial cell function.

F CLINICAL TRIALS AND GENE THERAPY

The ability to apply our laboratory and clinically based expertise through translational research to improve the health of our large patient population is a fundamental aim of the Medical School. This has been underpinned by two highly successful Clinical Trials Units and an innovative Gene Therapy programme.

The University of Birmingham Clinical Trials Unit (BCTU) (Gray, Wheatley, Clarke) was set up in 1997 (core funding NHS R&D West Midlands; £2.3m) to stimulate and support clinical trial research across a range of medical specialties (over 120 proposals already reviewed) as well as specialising in meta-analysis. Major trials include AD2000, a large, pragmatic trial assessing whether donepezil (Aricept) and aspirin produce worthwhile benefits in Alzheimer’s disease (NHS R&D), a large trial comparing dopamine agonists, MAOB inhibitors and COMT inhibitors, against established treatment with L-dopa in Parkinson’s disease (NHS HTA supported by Clarke), and a recently funded trial of surgery for advanced Parkinson’s Disease (MRC £1.5M; with Williams). Other in-house studies are ASTRAL, revascularisation of renovascular disease by balloon angioplasty, with or without stenting (AVE Medtronic), MRC acute myeloid leukaemia trials, LUNA, an RCT of laparoscopic uterosacral nerve ablation for women with chronic pelvic pain, and an RCT comparing different surgical techniques for rectal prolapse. BCTU also coordinates, with CRC Trials Unit, QUASAR (MRC £2M) and aTTom (CRC/ICRF/MRC), two UKCCCR ‘mega-trials’ of breast and colorectal cancer treatment.

Langman has studied sudden death in psychiatric patients, drug causes of pancreatitis, long term surveillance of omeprazole and selective COX-2 inhibitors through a European surveillance network (Birmingham, Newcastle, Spain, Sweden) and prevention of cancer by anti-inflammatory agents (Wellcome Trust, Biomed, MRC, Industry). Keighley designed and implemented multicentre surgical trials of bowel dysmotility. Research priorities in critical care medicine have been identified by Bion and colleagues. Sinclair’s research has focussed on quality of life and cognitive function in the elderly with common disorders such as diabetes and asthma. Miller’s studies focussed on clinical utility and international standards for pulmonary function testing. Kendall developed a unique system for the early diagnosis of common cancers via direct GP referral that is now widely applied in the UK. Outcome measures of success are now being defined and the patient base has been used for several community-based clinical studies (with members of UoA2 eg H.pylori epidemiology). Peters developed clinical laboratory information systems (notably TelePath Systems Ltd) and a rules-based computerised drug prescribing and administration system; all are facilitating optimal clinical practice. She has funding to develop a common IT support framework for all the UK Wellcome Trust CRFs. Thorpe and colleagues have developed enhanced chemiluminescent assays for antioxidant capacity in blood and are evaluating defects of antioxidant protection in clinical disease states such as diabetes and vascular disease.

Cancer Clinical Trials Unit. This CRC Unit is conducting large, randomised, phase III trials in colorectal (Kerr), breast (Poole), pancreatic (Dunn) and urological (James) cancers as well as collaborating in national and international studies. Kerr is directing an internationally competitive series of Phase III randomized clinical trials in colorectal cancer which include: the largest adjuvant chemotherapy trials ever completed (Quasar I and II, 6000 patients); hepatic arterial chemotherapy; novel chemotherapy schedules; systemic administration for advanced disease; maintenance trial with COX-2 inhibitors following surgery and adjuvant chemotherapy. Recent phase I and II trials in bladder cancer have lead to a national CRC-funded study of chemoradiotherapy in bladder cancer, and an international phase III trial of immunotherapy in prostate cancer (James) has been approved by the FDA. The Trials Unit is well-placed to utilise forthcoming developments in genomics and proteomics in existing and prospective clinical trials to evaluate the potential of new predictive and prognostic markers. Alongside clinical trials, the unit has developed and evaluated novel methods of assessing quality of life for patients being treated for cancer (Billingham); statistical support for the design and evaluation of trials data is provided within the unit (Dunn). Cullen is a key clinical collaborator involved in planning and implementing large multicentre trials in lung cancer, testicular tumours and lymphomas. Mann played a major role in describing the epidemiology of malignant disease in children and in leading multicentre clinical trials of childhood tumours (leukemias, germ cell tumours, neuroblastomas, Hodgkin’s disease). The innovative patient website CancerHelp UK (www.cancerhelp.org.uk) was developed by James and the late Tweddle and is now jointly run with CRC. This incorporates a patient-orientated trials database - a powerful tool for online patient recruitment and management. Research with Daniels (UoA68) is examining the patient acceptability and usefulness of this approach. Together with Benyon (Physics, UoA19), James has pioneered the development of Boron Capture to treat solid tumours. Other collaborators include Hobbs (UoA2) and a range of European (EORTC) and US collaborative trials groups (CALGB, NCCTG, SWOG). The Unit’s strategy is to translate developments from laboratory-based cancer research (UoA1) into collaborative phase III trial programmes and to foster clinical trials of gene and immunotherapy (funding from CRC, MRC, NHS R&D).

Gene Therapy. An MRC Co-operative Group (Translational Research: Gene and Immunotherapy of Cancer; to 2004) and substantial CRC funding underpin the progression of laboratory research into hypothesis-testing phase I clinical trials incorporating pharmacokinetic and pharmacodynamic studies. Gene therapy has centred upon use of E. coli nitroreductase, which confers sensitivity to the prodrug CB1954 (Searle, Mautner, Kerr, Neoptolemos with Young, UoA1). Adenoviral vectors have been developed to deliver the nitroreductase gene, and in collaboration with Cobra Therapeutics Ltd, phase I clinical trials have been initiated in the new Cancer Centre at Birmingham involving intratumoural injection of the virus, for patients with primary or metastatic liver cancer (with Candinas). Similar trials in patients with recurrent head & neck cancer, ovarian (Luesley) and prostate cancer (James) will commence shortly. Tumour selectivity may be enhanced by use of tumour-specific promoters to control gene expression; James and Searle developed a prostate-specific PSA promoter and the promoter of the L6 tumour antigen has been cloned (with Byrd, UoA1) and is being characterised. Searle is developing nitroreductase variants with improved activity, based on structural studies (with White & Hyde, UoA14 and Cobra Therapeutics). Animals cured of tumours by nitroreductase/CB1954 can reject tumour challenge, and enhancement of this by co-expression of GM-CSF is being explored (Searle, Young UoA1). The adenovirus fibre protein is being genetically modified to retarget the virus to novel receptors (Mautner, Searle with Moss, UoA1), and replicating, oncolytic adenoviruses are being developed for transgene delivery (with Young, Gallimore, Grand, UoA1). Cruickshank tested an oncolytic herpes simplex virus (ICP34.5 mutant) in patients with glioma, demonstrating safety and suggesting possible survival benefit (with Brown, Glasgow). Seymour’s group (CRC, BBSRC, EU Network funding) is developing novel, self-assembling polymer-based vehicles for DNA delivery; these have extended circulation times, raising the possibility for systemic delivery. With Mautner he used the HPMA polymers to coat adenovirus, which shields them from neutralising antibody present in many patients and permits retargeting by covalent attachment of novel ligands. These technological advances are increasingly being applied to ‘non-cancer’ gene therapy programmes of research, notably with Logan (UoA5) in studies applying gene delivery systems in neural regeneration and recovery (with neuroanatomist Berry, GKT, London). Axotomised neurons are being transfected with neurotrophic factor/receptor/anti-apoptotic genes to promote neuron survival and sustained long tract regeneration.

Immunostimulatory strategies for cancer therapy exploit the key role of dendritic cells (DCs); Adams, Kerr and Young (UoA1) found immune responses to hepatocellular carcinoma are present but suppressed in vivo; in a phase II study, patients with HCC have been treated with autologous DCs pulsed with tumour lysate. GTAC approval has been granted for phase II studies in metastatic melanoma using DCs transfected with plasmid encoding a polyantigen (with Cobra Therapeutics) and trials are planned for neoadjuvant immunisation against the mutant oncogene K-ras in colorectal cancer using DCs pulsed with a peptide vaccine (Bramhall with Steven, UoA1).

Mechanisms and practices for promoting research

Research in the School is managed by the Strategic Research Committee, facilitating identification of funding initiatives, strategic decisions on infrastructure development, space allocation, and support for multidisciplinary collaborations. The University devolved budgetary system has allowed high quality research to be supported in UoA3 through selective allocation of equipment (ca £120Kpa), recurrent funds (ca £250K pa), technical support and studentships (5/6 per year), based on research performance indicators (publications, research income, research students). Travel grants are provided for junior members of staff. New academic appointments are supported with studentship allocations, consumables and where appropriate technical support; clinical researchers have protected research time through agreed academic job plans. Clinical fellows undertake laboratory-based programmes supported by MRC, CRC, Wellcome Trust and other charities, producing a cadre of clinical scientists who are being appointed to redesigned clinical lecturer training programmes and subsequent Senior Fellowships, eg. Stewart and Buckley, MRC Senior Research Fellows. Five Clinical Lecturers have been returned as Category A staff, indicating the quality of their research and the School’s commitment to the future development of Academic Clinicians. In all research themes there is seamless integration with Category C staff.

Research Infrastructure

The existing laboratories in the Institute of Clinical Research on the QEH/Medical School site have been extensively refurbished through HEFCE and Endowment (£500K) support. An Institute of Biomedical Research (JIF £18.7M - Adams, Maher, Stewart, principal investigators) is under construction and will accommodate researchers focussing on mechanisms of host susceptibility and disease pathogenesis. Essential elements of this development are: (i) strong basic research in gene regulation, signal transduction, immunology, and virus-cell interactions, with links on campus to Structural Biology (JIF and JREI-funded NMR facility), Biological Chemistry and Bioinformatics (Biosciences, UoA14); (ii) clinical research in cancer susceptibility, genetic basis of neuropsychiatric disease, disorders of endocrine metabolism, and chronic inflammatory and infectious disease; (iii) a reconfigured research strategy allowing major initiatives in developmental genetics, protein phosphorylation, and hepatitis virus infection. The IBR will link to a new West Wing extension housing the multidisciplinary Cardiovascular Science initiative. The adjacent Wellcome Trust Clinical Research Facility (CRF) (1 of 5 awarded nationally) will promote high quality clinical research linked to strong basic science expertise and be a focus for clinical training fellows and lecturers. NHS R&D resources will be focussed to the facility, designed for intensive clinical investigations and delivery of novel therapies, thereby promoting translational studies at the interface of basic and clinical research. Co-directors of the CRF are Stewart and Neuberger (R&D Director) with Savage as Programme Manager. Principal Investigators are Adams, Bacon, Franklyn, Kerr, Savage, Sheppard, Stewart and collaborators from UoA1. The CRF will be an integral component of a major NHS facility for Cardiac Surgery and Head and Neck Cancer. A new 1000 bed University Hospital (£291M) will be built alongside the Medical School by 2007, which will provide the focus for high quality clinical care for patients with common and complex diseases. This decision makes Birmingham one of the very few UK universities with Schools of Medicine, Biosciences and Chemistry clustered alongside the major Teaching Hospital on a single campus.

Research student facilities and mentoring.

The Graduate Research School actively manages training and supervision of all research students. Seminars include supervisory and monitoring arrangements, bibliographical management, statistics, use of data-bases, scientific writing, presentation and teaching skills, scientific ethics, animal experimentation, and careers in academic medicine and industry. Graduate School Research Workshops emphasise School-wide research themes and techniques. An annual Graduate Student Day allows presentation of posters by students in presence of all supervisors. Each student has one or more supervisors and all Divisions at least three Higher Degrees Tutors. The School offers a very successful BMedSc course, offering Medical Students the opportunity for a period of laboratory-based research as well as producing high quality science students for recruitment to research studentships. This approach is endorsed by recurring MRC Studentship allocations to UoA3.

Interdisciplinary/collaborative research

The restructuring of the Medical School into 6 Divisions, the Strategic Research Committee, the opening of the Wellcome Trust CRF, the JIF-funded IBR and National NMR Centre, the completion of the Cancer Institute build, the close proximity of the School of Biosciences, and the integrated clinical academic units (Medical School/Trust) all strongly promote interdisciplinary and collaborative research. All major research programmes involve international collaborations with sharing of expertise and reagents, sabbatical visits to and from Birmingham (supported by Divisional funds) and representation on European and USA societies and agencies.

Industry/commerce relationships; Government policy

Collaboration with industry is apparent in all research areas, illustrated by gene therapy trials, use of a designated Clinical Investigation Unit for phase 3 clinical trials, developments from the Wolfson Applied Technology Laboratory, availability of extensive patient populations and databases, and the funding of the BCTU. Industry funding has allowed senior research appointments to programmes headed by Sheppard/Stewart, Kerr, Adams, and Stockley. The Medical School has made significant contributions to R&D applications from local Trusts and has been particularly influential in determining National cancer research priorities. The importance of cardiovascular disease in health priorities is reflected in the recruitment of Bradbury, the new BHF Chair and the extensive involvement in community-based projects with UoA2. 11 patents are held by researchers within UoA3. Biotechnology companies have been developed by Thorpe (Mermaid Diagnostics), Seymour (Hybrid Systems) and Kerr (Cobra Therapeutics) and many researchers have benefited through collaboration with Bradwell (Binding Site, Birmingham).

Development and support

All research groups have identified lead researchers who monitor work in progress and set new goals through weekly meetings. Individual research performance is monitored through biannual appraisal involving an independent appraiser. Weekly seminar meetings are held by all groups, which include presentations from clinicians and basic scientists in training, a proportion of which are organized and chaired by young researchers. Formal Divisional research away-days allow for setting of research priorities which are explicit and owned by all.

Self Assessment

The integration of clinical and basic science researchers has proceeded at a rapid pace as outlined in our 1996 return and is explicit in the new Divisional structure. Research support from NHS colleagues has been key and promised clinical service developments in liver and renal medicine, oncology and neurosciences have occurred. Clinical academics in neuroscience have led important initiatives in clinical care, but the major research focus in this area has shifted to the support of a strong laboratory-based molecular genetics and neural network programme (see UoA5). Research developments in hepatology, rheumatology, oncology, endocrinology and medical genetics have been particularly successful as a result of strategic investment, grant funding and appointment of high quality researchers. Access to large Regional patient populations has been strengthened through collaborative projects with community disciplines (UoA2). The successful establishment of BCTU, headed by Gray (collaborator in 1996) has had an energising effect on clinical trials in a number of disciplines. Computerised clinical databases have been used with increasing success providing substantive epidemiological data from the Region’s large population. The MRC-funded Centre for Clinical Research in Immunology and Signalling has been superseded by the MRC Centre for Immune Regulation, in which Buckley, Bacon, Adams and Savage provide the main clinical focus, resulting in substantial collaborations between UoA1 and 3. The NHS-funded Cancer Institute Extension has been opened and gene therapy trials have commenced.


Users of this website should note that the information is not intended to be a complete record of all research centres in the UK

Copyright 2002 - HEFCE, SHEFC, ELWa, DEL

Last updated 17 October 2003

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