Cardiology

Project Lead: Dr Maciej Tomaszewski (mt142@le.ac.uk) and Professor Nilesh J Samani (njs@le.ac.uk)

Low-frequency alleles and genetic susceptibility to cardiovascular disease

Coronary artery disease and its major risk factors (hypertension and hyperlipidaemia) are complex multi-factorial disorders with a significant heritable component. Recent genome-wide association scans (GWAS) have revealed several common (minor allele frequency >5-10%) variants that increase the risk of these diseases. Leicester has made a significant contribution to these efforts (1-3). However, collectively the identified alleles explain only a modest proportion (10-15%) of the heritability of these disorders. One possible source of the “missing” heritability could be lower frequency (<5%) alleles with large effects on the phenotype. This project will combine available resources (GWAS data) with new bioinformatic strategies based on 1000 Genomes project as well as novel data generated through next generation sequencing and exome SNP-based arrays to investigate this possibility. The project will provide the ACF with excellent training in genetic and bio-statistical/bioinformatic techniques and involvement in research that is at the forefront of work in this field internationally. Scientifically, the project will not only identify novel genes affecting risk of cardiovascular disease and improve our understanding of its genetic architecture but will also address one of the major unanswered questions in complex trait genetics – whether rare variants may explain “missing heritability” of such conditions.

Relevant References:

 1.       Samani NJ, Erdmann J, Hall AS, et al. Genomewide Association Analysis of Coronary Artery Disease. N Engl J Med 2007; 357:443-453.

2.       Tomaszewski M, Debiec R, Braund PS, et al. Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array. Hypertension 2010;56:1069-76.

3.       Schunkert H, König IR, Kathiresan S et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011;43:333-338.

Clinical Oncology

Project Lead: Professor Paul Symonds (rps8@le.ac.uk)

NEK11 and response to pre-operative chemoradiotherapy in rectal cancer

Project Outline

This will be a joint project between Oncology (Professor P Symonds, Dr S Vasanthan and Dr A Osman), Pathology (Dr K West), Surgery (Mr D Hemingway), University Department of Biochemistry (Professor A Fry) and Radiology (Dr D Jones).  Professor Fry already has a PhD student in post to carry out the NEK11 assays.  Patients suffering from rectal cancer have a biopsy taken at a sigmoidoscopy.  A portion of this biopsy will be sent to Professor Fry’s laboratory for assay of NEK11 prior to chemoradiotherapy.  Patients will get standard chemoradiotherapy prior to surgery.  This is normally 45 Gy in 25 fractions with oral capecitabine chemotherapy.  The tumour will be resected by Mr Hemingway’s team in a standard fashion.  The response to chemoradiotherapy will be assessed by Dr West.  The degree of cancer regression will be scored using the following grading system:

1. Complete tumour sterilisation

2. Microscopic foci of adenocarcinoma remaining with marked fibrosis

3. Marked fibrosis but macroscopic disease present

4. Little of no fibrosis but with abundant macroscopic disease

We will correlate the pathological outcome with NEK11 levels.

Duties of ACF

The ACF will be responsible for co-ordinating the collection of pre-chemoradiotherapy biopsy specimens and working with Professor Fry in the Biochemistry Department on NEK11 assays.  The successful candidate will be taught how to score response to chemoradiotherapy by Dr West.

Diabetes

Project Lead: Professor Melanie Davies (melanie.davies@uhl-tr.nhs.uk)

Type 2 Diabetes in Adults aged under 40 years.

Type 2 Diabetes in Adults aged under 40 years. Levels of obesity and average BMI have risen dramatically in young adults and adolescents in the last decade.  One of the most deleterious consequences of this has been a dramatic increase in the prevalence of T2DM in younger age groups. T2DM in the young is associated with an extreme phenotype characterised by high levels of obesity and is associated with a high risk of mortality and morbidity. T2DM in the young has consistently been found to be associated with high levels of obesity, poor levels of glycaemic control and high levels of adverse outcomes. The risk of myocardial infarction in early-onset T2DM (<45 years) is 4-fold higher than in late onset T2DM (>45 years) and 14-fold higher than in people without diabetes A mortality rate of 9% has also been observed over a 9-year period in young persons with T2DM. We have an ongoing study within in Leicester, funded by the MRC, has also demonstrated that young adults (< 30 years) with T2DM are further characterised by: extremely low levels of cardiorespiratory fitness, higher left ventricular mass/volume ratio, lower body surface corrected end diastolic volume, vitamin D deficiency and increased chronic low-grade inflammation. These alarming figures highlight the urgent need to develop and evaluate optimal medication treatment pathways in this group. The inability of current treatment pathways to target obesity as well as dysglycaemia in this population is likely to be on of the contributing factors to findings from ongoing qualitative research undertaken by our research group where young individuals with T2DM have reported feeling highly dissatisfied with their current levels of treatment and have poor self-esteem. Recent advances in the management of T2DM in adults include GLP-1 analogue therapy. GLP-1 analogue therapy has been shown to promote substantial weight loss over time, with greater reductions occurring in those with higher BMI at initiation. Our proposed study aims to bridge this gap in the evidence and work towards providing a desirable treatment pathway for this growing, but currently neglected, high risk group. This could help to alleviate the substantial clinical and financial burden on the NHS that will be associated with growing prevalence of type 2 diabetes in the young. The proposed project will be to develop and to investigate the benefits of particular glucose lowering therapy such as the use of GLP analogues on glycaemia control, weight and cardiac function in this group by carrying out a pilot study. We will investigate effect on novel secondary outcomes such as cardiac function.  Given we have demonstrated serious cardiac abnormalities and low-levels of cardiorespiratory fitness in young adults with type 2 diabetes, these outcomes are highly clinically relevant in this group.

Gastroenterology

Project Lead: Professor Janusz Jankowski (j.a.jankowski@qmul.ac.uk)

Colonic Adenocarcinoma Prevention Program-4

Patients with ulcerative colitis (UC) have an increased risk of developing colonic carcinoma. This complex disease occurs because of genetic susceptibility, initiation of chronic mucosal inflammation by agents such as bile acids and pathogenic bowel bacterial flora. There is evidence that Ursodeoxycholic acid (URSO) maybe chemopreventive by abrogating bile acids. The CAPP-4 trial will be the largest randomized control trial in the world in UC. The 2-year pilot phase of this trial will involve recruitment of 200 UC patients (total target 3500). Patients will be randomized to 2 arms; active URSO or placebo. Outcomes will be relapse rates, degree of inflammation, and development of dysplasia. Recent UHL trust approval and sponsorship for the trial has been obtained.

The ACF will help implement the pilot study, undertake dedicated research clinics for recruitment and follow-up (with expert training) and help provide a dedicated standardized surveillance colonoscopy using chromoendoscopy. They will integrate several sub studies compatible with UofL research strategy such as: collection of bloods for SNP analyses of prediction/prognostication; collection of tissue for proteomics of predictive biomarkers; collection of stool samples for biotic studies. The ACF will analyse and publish in peer-reviewed journals and this will then form the basis of a higher degree and a possible fellowship application.

General Practice

Project Lead: Professor Kamlesh Khunti (kk22@le.ac.uk)

Management of microalbuminuria in people with Type 2 diabetes in Primary Care

All major international guidelines emphasise the importance of prevention of complications of type 2 diabetes mellitus (T2DM), however, little progress has been made in this area in contrast to the clinical care of established complications. People of South Asian (SA) origin are a substantial minority ethnic population in the UK and have a higher prevalence of premature CHD and T2DM. Early nephropathy, known as Microalbuminuria (MA), in people with T2DM, particluarly in SA populations, has been shown to be a strong risk factor for development of renal disease and is an independent predictor of cardiovascular morbidity and mortality. One major intervention study has shown that a multifaceted intervention can reduce cardiovascular morbidity, mortality and deterioration in renal disease. However little progress has been made in this area since the publication of this major trial. This proposed programme of research has a number of objectives. Firstly, we will determine current screening and management strategies of people with MA and T2DM in primary care by looking at routine clinical data in Leicestershire practices and report epidemiology of MA in primary care. Finally we will conduct qualitative interviews with four general practitices about the fesibility of conducting a an intervention of tight control of cardiovascular risk factors together with a structured self management education programme in people with T2DM and MA in primary care.

Geriatrics

Project Lead: Dr Simon Conroy (spc3@le.ac.uk)

Blood pressure in frail older people

Blood pressure (BP) management in older people has been highlighted by the HYVET study1, which demonstrated that BP control in a robust population of community dwelling older people saved lives. But not all older people are the same: those aged 85+ have a median of five comorbidities and 80% have limitations in activities of daily living2. Orthostatic hypotension which accompanies hypertension in 30% of older people3 4 may be exacerbated by anti-hypertensive therapy3, and is associated with vascular mortality5 and all-cause mortality6. In a population of frail older people, events such as falls, fractures and institutionalisation are the dominant issues8 9. There are reasonable grounds to question if treating hypertension in a population of frail older people is beneficial.

We propose to determine if anti-hypertensive withdrawal improves quality of life and outcomes for frail older people.

This work will involve a developmental project and feasibility RCT lasting 2-3 years (RfPB application 10/2011), followed by a large multicentre trial.

Geriatrics

Project Lead: Dr Amit Mistri (akm17@le.ac.uk)

Advance Care Planning across the spectrum of cerebrovascular disease – A qualitative pilot study of patients and carers

Advance Care Planning (ACP) is an intrinsic component of the NHS End of Life Care Programme, and is "a voluntary process of discussion about future care between an individual and their care providers", with the intention of establishing preferences in relation to future healthcare.  ACP is useful in determining best interests, especially where the individual loses mental capacity.

Transient Ischaemia Attacks (TIA) and strokes are a marker for high risk of future stroke.  The extent of appreciation of this risk by patients/carers, and preferences for ACP are uncertain.  Moreover, stroke is commonly associated with various impairments that limit mental capacity, and ACP can aid in establishing best interests.

We propose a pilot study of people following a TIA/stroke (and their carers) to establish

(i)      Patient/carer awareness of future stroke risk

(ii)    Views on ACP

(iii)   Specific issues around severe stroke, including current provision and unmet need for palliative care.

We will recruit ~30 people from the Specialist TIA clinic and Stroke Services in the Leicester Hospitals.  The study will involve a series of qualitative interviews over a one-year period, with an iterative process to establish themes in advance care planning specific to people following a stroke or TIA.

Haematology

Project Lead: Dr Simon Wagner (sw227@le.ac.uk)

Mechanisms of cell resistance to chemotherapy in chronic lymphocytic leukaemia and low-grade lymphoma

One cause of treatment failure in chronic lymphocytic leukaemia and the low-grade lymphomas is robust survival and resistance to current chemotherapy of the malignant cells within lymph nodes and the bone marrow. In lymph nodes CLL cells exist in a microenvironment consisting of stromal cells, T-cells and growth factors. A hypothesis to explain increased leukaemic cell survival in lymph nodes is that signals from the microenvironment components stimulate pathways leading to increased pro-survival protein expression. Utilising a cell culture system to mimic the components of the microenvironment we have shown that increased survival is due to a switch in BCL2 family pro-survival protein expression (Willimott S, et al. Br J Haematol 2007 Sep; 138(6): 721-732) from BCL2 itself to BCL2A1 and BCL-XL. We now propose to analyse in detail the mechanisms responsible for the changes in BCL2 family protein expression by means of known and novel inhibitors of regulatory pathways. In particular we are currently focusing on how control of translation by the microenvironment leads to resistance to both spontaneous and drug induced apoptosis. The ACF project will involve short term cultures of leukaemic cells in order to assess the effects of novel drug combinations on leukaemic cell survival. There is interest in targeting the microenvironment for therapy in CLL and the results of the project may suggest novel avenues for treatment.

Infectious Diseases

Project Lead: Professor Karl Nicholson (karlgnicholson@doctors.org.uk)

This project seeks to extend a small pilot study that was recently carried out at the University Hospitals of Leicester NHS Trust (Leicester Royal Infirmary) with promising results. The proposed study is currently undergoing ethical review. It sets out to develop a human model of transmission of common respiratory viral pathogens in the health-care setting, with two ultimate goals – first  to assess the frequency of transmission of influenza, RSV, and entero-rhinoviruses following brief close contact of young adult volunteers during exposure to young infected children in a healthcare setting – it will then be used to assess the importance of aerosols, droplets, and fomites as routes of transmission (to inform clinical practice),  and – second, as longer term objectives: (a) to assess the potential role of new inhibitors (as therapy or prophylaxis) against natural infection with RSV, entero-rhinoviruses, and influenza, and (b) to improve our understanding the pathogenesis of naturally acquired respiratory viral infection. The need for a better understanding of the role of aerosols in the transmission of influenza has been highlighted both nationally (the UK Departments of Health), and internationally, e.g., by the US Centers for Disease Control and Prevention. This information is considered extremely important in informing clinical management, notably with respect to the use of different types of personal protection (e.g., surgical masks versus N95 masks, eye protection, gloves) during pandemic influenza when vaccines and antiviral prophylaxis are unavailable or are reserved for treatment only. The ACF will oversee the clinical aspects of the research, i.e., he/she will enrol index cases and volunteers, oversee the ‘interaction’ between volunteers and index cases, collect specimens for diagnostic purposes, and will carry also carry out multiplex reverse transcriptase polymerase chain reaction diagnostic tests on stored specimens, after a period of training.    

Medical Microbiology

Project Leads: Professor Mike Barer (mrb19@le.ac.uk) and Dr Kumar Rajakumar (kr46@le.ac.uk)

Can high-definition microbiota profiling of specimens from patients with respiratory diseases inform better patient management?

 The respiratory airway diseases asthma and chronic obstructive pulmonary disease (COPD) affect over 400 million people world-wide and cause considerable morbidity and mortality, while the lung pathology associated with cystic fibrosis is the commonest cause of death among patients with this inherited disorder. Besides host factors, infection and/or colonization of the respiratory tract has long been recognized as a major contributing factor to clinical exacerbations, persistence and/or disease progression. At Leicester Professors Barer and Brightling have pioneered a range of culture-independent, molecular technologies to profile the bacterial microbiota present in respiratory specimens obtained longitudinally from these patients. These analyses have led to exciting insights into the complexity of the microbiota, transitions during switches from stable to exacerbation states, and putative novel organisms associated with exacerbations, and a high-impact publication (Bafadhel et al AJRCCM 2011). Recently, high-throughput sequencing has provided even higher resolution of microbial communities being studied. Exploitation of this technology for metagenomic and metatranscriptomic analyses will permit not just definition of species profiles, but microbial gene complements and gene expression patterns associated with samples. The central hypotheses to be investigated are do disease-specific microbiota biomarkers exist, do these predict clinical state and can this information guide highly targeted treatment? The ACF in Medical Microbiology will join an active team of researchers with NIHR and MRC funding who are engaged in this world-leading project. Leicester has a strong track record of clinical training in microbiology, and both Microbial Science and Respiratory Science are priority research areas in the Medical School, and so the successful candidate will be well supported in their scientific, academic and clinical training.

Medical Oncology

Project Lead: Dr Julian Barwell (jgb8@le.ac.uk)

Familial Cancer susceptibility in Black and Minority Ethnic groups

The incidence of breast and bowel tumours is steadily rising nationally and there has been over a 400% increase in referrals to the Leicestershire familial cancer susceptibility service in the last ten years.  We have expressed concerns about rising rates of bowel cancer in young South Asians locally, which are usually very low in their country of biological origin. However, throughout the United Kingdom the referral rates to Clinical Genetics for a family history of cancer are lower than expected from Black and Minority Ethnic groups, possibly indicating inequality of access to healthcare.

We have large BME population in Leicester city which is expected to approach 50% in the 2011 census. However, in the East and West Midlands, familial cancer referral rates are only 11%. This inequality of access and its subsequent impact is something we are addressing alongside and part of the National Organisation, the Genetic Alliance.
Aims: 
1) Determine trends of cancer referrals from BME populations in regional Clinical Genetics centres over time 
2) Determine cancer rates in the local and national BME groups 
3) Assess the impact of this inequality of access by measuring screening uptake, molecular diagnostic testing and stage and grade of cancer and detection of tumours at presentation.

4) Explore why there are lower referral rates from our local community at cancer road shows alongside CRUK and Macmillan. 
5) Consider reassessing family history of cancer referral criteria and access to clinic in light of language barriers and potentially lower cancer rates in relatives living in South Asia.

Medical Oncology

Project Lead: Dr Anne Thomas (at107@le.ac.uk)

“Expertise in the coordination of early phase studies in Oncology including first in human and pharmacodynamic phase I/II studies”

In 2012, the new Hope Unit at the Leicester Royal Infirmary will open. This is a purpose built Clinical Research Unit where cancer patients undergoing early phase clinical studies are treated.  Leicester is the only phase I Unit in the East Midlands dedicated to treating Oncology and Haematology patients, and one of a limited number of centres nationally.  The portfolio includes first in human clinical studies, dose escalating phase I studies and complex phase II studies evaluating pharmacodynamic biomarkers.

The ACF will be based on the Hope Unit and have a unique opportunity to gain considerable experience in the management of patients undergoing phase I studies.  It is envisaged that the ACF would spend 25% of their time on academic activities and 75% clinical.  The academic project would be to lead on a phase I study being run through the Astra Zeneca/ECMC partnership looking at the combination of a pan ERB inhibitor in oesophago-gastric cancer.  This would involve all aspects of trial management from ethics, to recruitment of patients, participation in dose-escalation teleconferences report and manuscript writing.

This is a clinical project suitable for a candidate wanting a career in Medical Oncology with specialisation in early phase trial design. 

Paediatrics 

Project Lead: Dr Erol Gaillard (eag15@le.ac.uk)

Identification of features that predict hospital admission with acute asthma in children.

Background:   Acute exacerbations of asthma are one of the commonest reasons for hospital visits and admission in children.   The economic burden of acute asthma and the impact on families and affected children is considerable.   Despite nationally and internationally renowned asthma services in adult and paediatric respiratory medicine, Leicestershire has some of the highest acute asthma admission rates in the country (Asthma UK data 2010).   Very little research examining factors that predict exacerbations in children has been published.

The Leicester Cohorts were established between 1985 and 1998 with the broad purpose of studying the childhood epidemiology of wheezing disorders and other common respiratory problems. The Leicester cohorts provided the first data on prevalence and natural history of preschool wheeze in Europe.   Several discrete wheezing phenotypes in preschool children, identified through the analysis of questionnaires returned by members of the Leicester cohort, have recently been published.   This is important as the highest admission rates are in children with preschool wheeze.

Methods:   Using the extensive database that exists of the Leicester cohort and searching through admission data from the Leicester Royal Infirmary we will:

1.      Define children at particular risk of severe exacerbations requiring hospital admission.

2.      Identify phenotypes most associated with hospital admissions.

3.      Study at risk children in more detail with respect to the development of allergy, lower airway inflammation, respiratory function and bronchial hyperresponsiveness.

Respiratory Medicine

Project Lead: Professor Peter Bradding (pb46@le.ac.uk)

MS4A family proteins as novel therapeutic targets in mast cell-dependent pulmonary disease

Background

Mast cells play a key role in asthma and pulmonary fibrosis through their interactions with structural cells such as airway smooth muscle and parenchymal fibroblasts respectively.  Mast cells express several members of the MS4A family of transmembrane proteins. MS4A2 is the beta chain of the high affinity IgE receptor. The role of other MS4A family members is poorly understood, but some have been proposed to act as ion channels of ion channel modulators. 

Project outline

Our hypothesis is that MS4A proteins play key roles in human mast cell biology, regulating mediator release, migration, proliferation and survival. The principal aim of this project is to identify the functional role of the MS4A proteins present in human lung mast cells, and their role in mast cell biology of relevance to asthma and pulmonary fibrosis. Techniques which will be taught and used include patch clamp electrophysiology, real-time quantitative PCR, Western blotting, immunohistochemistry and functional biological assays.

This post would be suitable for applicants wishing to pursue a career in respiratory medicine or allergy, or other medical specialities. The research work will be supervised by Professor Peter Bradding.

Respiratory Medicine

Project Lead: Professor Peter Bradding (pb46@le.ac.uk)

Transient Receptor Potential (TRP) ion channels as novel therapeutic targets in mast cell-dependent pulmonary disease

Background

Mast cells play a key role in asthma and pulmonary fibrosis through their interactions with structural cells such as airway smooth muscle and parenchymal fibroblasts respectively.  Secretion of mast cell mediators requires influx of extracellular Ca2+. Ion channels represent attractive therapeutic targets. Human lung mast cells express many members of the Transient Receptor Potential (TRP) C, M and V families of ion channels, but their function has not been characterised.

Project outline

Our hypothesis is that TRP channels play key roles in human mast cell biology, regulating mediator release, migration, proliferation and survival. The principal aim of this project is to identify the functional TRP channels present in human lung mast cells, and their role in mast cell biology of relevance to asthma and pulmonary fibrosis. Techniques which will be taught and used include patch clamp electrophysiology, real-time quantitative PCR, Western blotting, immunohistochemistry and functional biological assays.

This post would be suitable for applicants wishing to pursue a career in respiratory medicine or allergy, or other medical specialities. The research work will be supervised by Professor Peter Bradding.

Respiratory Medicine

Project Lead: Professor Andy Wardlaw (aw24@le.ac.uk)

Characterisation of the clinical significance of fungal associated airways disease

Hypothesis: The overall hypothesis being tested in this project is that a significant cause of lung damage (bronchiectasis and irreversible airflow obstruction), in asthma is the colonisation of the bronchial tree with filamentous fungi, mainly of the Aspergillus and Penicillium genera in particular Aspergillus fumigatus. The specific hypothesis is that sensitisation to specific fungal allergens which cross-react with human allergens is a particular risk factor for damage.

Background: IgE sensitisation to fungal allergens and a positive sputum culture for a filamentous mould, particularly A.fumigatus, are common features of severe asthma as is a positive sputum culture for a filamentous mould.  We and others have found that sensitisation and/or culture are associated with a reduced post-bronchodilator FEV1 and an increased prevalence of bronchiectasis, in the absence of florid features of allergic bronchopulmonary aspergillosis. Some fungal allergens are homologues of human proteins raising the possibility of an auto-immune component to fungal allergy which might explain why tissue damage occurs.

Plan of investigation: To further explore the relationship between fungal sensitisation and colonisation in asthma we will establish a longitudinal cohort of patients with asthma consisting of four groups of subjects. IgE sensitised to fungi and culture positive, either of these or neither of these.  The patients will undergo detailed phenotyping at the outset of the study and will have six monthly visits thereafter for a total of five years.  The primary outcome of the study will be the relative rate of lung function decline between the groups. The ACF would be involved in setting up this cohort with specific responsibility for a cross-sectional assessment of the link between specific fungal allergens and lung damage.

Vascular Surgery

Project Lead: Dr Ed Choke (ec172@le.ac.uk)

Aortic aneurysm morphology score to predict the risks of reintervention after endovascular aneurysm repair

Endovascular aneurysm repair (EVAR) is currently the treatment of choice for large abdominal aortic aneurysms (AAAs). At present there is no method of identifying patients at risk of developing complications after EVAR. Therefore lifelong surveillance is necessary for all EVAR patients to detect and treat EVAR complications such as graft migration, kinking, fracture, endoleaks and limb outflow impairment. This carries the burden of lifelong hospital appointments, is costly and involves radiation risks if CT surveillance is employed. Ultrasound surveillance is safer and therefore used in preference to CT scans in some centres but is limited to high volume units.

Preliminary data from our institution have shown that AAA morphology can predict risks for complications needing reinterventions after EVAR. A model that can accurately stratify EVAR reintervention risks could be used to target surveillance to high risk EVAR patients.

This is a collaborative retrospective study of EVAR patients from Leicester and St George’s Vascular Institute. These patients will be randomly divided into development and validation sets. Multivariate logistics regression analyses of morphology variables (obtained through state-of-the-art CT reconstructions) will be applied to the development set. The aim is to create a morphology score that can predict reintervention risks. The accuracy of this model will be tested against the validation set.

It is anticipated that pilot data from this project will form the basis of future applications for grants and a fellowship for higher degree. A natural extension could be a randomised controlled trial to evaluate imaging surveillance versus clinic follow-up of EVAR patients at low risk of reintervention.