Clinical Research Office Sheffield Teaching Hospitals & University of Sheffield Baseline Research Strategy Identification, May 2011 Introduction The Joint STH/UoS Clinical Research Office is examining approaches to increasing Sheffield’s rate of success in attracting research funding. As an initial step, we would like to establish the basic structure of each Directorate’s approach to research, identifying the themes being pursued, the researchers working in each area, and the projects that are supporting the strategy. We should therefore be grateful if you would be kind enough to complete the table below, referring where appropriate to the associated Excel list of projects that are on record as being conducted during the last five years. To help establish a comprehensive view of your strategy please provide as much information as possible. Basic Information Please provide basic information about this data-collection exercise STH Directorate Respiratory Medicine Completed By Professor Moira Whyte (Research Lead and Theme 3), Prof Ian Sabroe (Theme 1), Dr Robin Condliffe (Theme 2), Prof David Fishwick (Theme 4), Drs Edenborough/Wildman/Pirzada (Theme 5), Drs Bianchi/Hughes (Theme 6) Approved By Date Completed 11th July, 2011 Research Themes Please identify each of the main areas in which your Directorate is actively conducting research # Theme name Basic Concept Stage Key Investigators (Basic, Translational, Clinical, Health Services Research, Industry) 1 Airways Disease Understanding how innate and Basic, Translational, Clinical I. Sabroe, R. Lawson, M. adaptive immunity might be Industry Whyte, J. Wild, S. Renshaw, targeted to improve outcomes in S. Walmsley and asthma and COPD collaborations with Professor David Dockrell in Infectious Diseases 2 Pulmonary Vascular Investigation of aetiology, Basic, Translational, Clinical D. Kiely, R. Condliffe, C. pathogenesis and treatment of Industry Elliot, A. Lawrie patients with pulmonary vascular (Cardiovascular Sciences disease both primary and TUOS), J. Wild (Radiology, secondary TUOS), I. Sabroe, M. Whyte 3 Interstitial Lung Diseases Investigation of aetiology, Basic, Translational, Clinical M. Whyte, S. Bianchi, S. pathogenesis and treatment of Industry Renshaw, S. Walmsley interstitial lung disease 4 Occupational Lung Investigation of aetiology, Clinical D. Fishwick, C. Barber, A. Disease pathogenesis and management Curran (HSL) of occupational lung disorders 5 Infection and Immunity Investigation of host-pathogen Basic, Translational, Clinical M. Whyte, I. Sabroe, F. interactions in the lung, with Industry Edenborough, M. Wildman, application to bronchiectasis, CF D. Dockrell, S. Renshaw, O. and airway disease Pirzada 6 Ventilation Clinical use of ventilatory Clinical, Industry S. Bianchi, R. Hughes strategies in diseases including neuromuscular and cardiac diseases Historical Research Strategy 2006-2011 For each theme, please describe your research strategy during the last five years. Identify the conceptual direction, the detailed approach to progress and your targeted funding bodies (e.g. NIHR, Portfolio Charities, Industry, etc.). The Respiratory Research Executive has identified 6 research Themes. Themes 1-4 are well established with ongoing programmes. Themes 5 and 6 are established, with studies both completed and in progress, but are still in development. 1. Airways Disease The airways inflammation theme is the flagship of basic and translational research in respiratory medicine. A series of investigations have explored how infections and other immune activators might cause airway inflammation in health and in disease, with research focused mainly around the mechanisms by which infections exacerbate asthma and COPD. The Sheffield group has produced internationally regarded science and has attracted major MRC and Wellcome funding for translational research. Prof Ian Sabroe (MRC Senior Clinical Fellow 2004-2009, the first MRC Senior Fellow in respiratory disease for approx. 15 years) has conducted a series of studies exploring how inflammation is established, modelling the airway in vitro. His more recent work is translating this by creating new human models of inflammation (challenging human volunteers in vivo with inflammatory stimuli), creating novel anti-inflammatory agents (SAPS, published 2008), and studying the biology of respiratory viruses. His work is currently funded by major grants from the MRC and Wellcome Trust, with other support from Asthma UK and Heart Research UK. Prof Moira Whyte has driven the establishment of one of the most respected respiratory science groups in the UK, recruiting Ian Sabroe, Stephen Renshaw, Sarah Walmsley, and establishing robust collaborations with Infectious Diseases, particularly through Prof David Dockrell. Her work, including major MRC funding held with Ian Sabroe, and supporting the Wellcome funding of Sarah Walmsley, has focused on the biology of lung inflammation. The collaborations within the group have led to important roles in a major MRC/ABPI COPD consortium. Dr Stephen Renshaw, current MRC Senior Clinical Fellow, has established a unique basic science model of inflammation in the zebrafish, and is currently actively collaborating with pharmaceutical companies to use this to screen for novel anti-inflammatory therapies, as well as exploring basic models of disease. He holds extensive MRC funding, and funding from the EU FP7 programme. Dr Sarah Walmsley (Wellcome Intermediate Fellow) has produced outstanding work determining how hypoxia, and a specific protein, PHD3, has contributed to the regulation of neutrophilic inflammation. She is highly respected in the field of how hypoxia contributes to airway inflammation, holding a prestigious Wellcome Fellowship, and co-supervising an MRC Clinical Training Fellow (Dr Roger Thompson). Prof David Dockrell (Infectious Diseases) is a key group collaborator, establishing numerous programmes of research with all the principal investigators listed here. His work on host-pathogen interactions in pneumococcal pneumonia is highly respected internationally, and his exceptional expertise in pathogen biology has enabled and driven exciting strands of research determining how infections modulate lung disease. Dr Rod Lawson (Clinical Lead for COPD) has collaborated with Prof Jim Wild using MRI imaging to study regional ventilation and perfusion in COPD, funded by GSK. He has also contributed patients and expertise to a number of industry-funded clinical trials in COPD and has previously held HTA funding for a large trial in pulmonary rehabilitation. A recent PhD student won a European Respiratory Society prize for work on swallowing in COPD. We have a major and extensive focus on airway inflammation, with significant expertise in understanding how inflammation happens, how we control infections, and how these processes are dysregulated to cause disease. Work through our participation in the MRC/ABPI COPD consortium will explore how local inflammatory responses are dysregulated in disease. This study will entail research bronchoscopies, skin inflammation models and blood sampling of patients and both smoking and non-smoking controls. We have also developed new ways of studying inflammation. We have created a new skin model which allows inflammation to be explored in healthy volunteers. We are using our unique experimental models of skin inflammation to study basic mechanisms of leukocyte recruitment to and persistence at inflamed sites (HRUK Clinical Training Fellow) and aim to establish an experimental programme involving LPS-mediated induction of airway inflammation. We plan to study defects in alveolar macrophage function in other specific disease areas, including HIV (MRC Clinical Training Fellow) and IPF (ACF in Respiratory Medicine). Funded by a Wellcome Clinician Scientist Fellowship, we also study patients with rheumatoid arthritis since their joint fluid is a source of large numbers of inflammatory cells. Further developments over the next 5 years will include study of alveolar macrophages from patients with pneumonia. In order to tackle the problems of airway inflammation, which underpin common diseases such as asthma and COPD, we have assembled a team of translational clinicians to develop novel research strategies targeting these processes. Aims and outputs are illustrated here: acute pneumonias are associated with an increased risk of myocardial infarction (MI), which is likely to be underpinned by actions of the cytokine IL-1. A translational approach led by cardiovascular sciences examined how IL-1 contributes to heart damage after the heart attack. We are now exploring, using our human models, the roles for IL-1 in human inflammation and whether we can predict who might be at risk of heart attacks, particularly in patients with respiratory disease. In work funded by the Wellcome Trust we are also developing new inhibitors of inflammation that we hope may be of benefit for patients. 2. Pulmonary Arterial Hypertension The Sheffield Pulmonary Vascular Disease Unit (SPVDU) is one of the largest units specialising in pulmonary vascular disease in Europe, with a referral population in excess of 15 million. During the last 5 years research has focussed on 4 main strands: 1. Detailed Clinical Phenotype and Bioresource, 2. Pulmonary and Cardiac Functional Imaging, 3. Pre-clinical models and discovery science, 4. Industry-sponsored clinical trials. Strand 1: We have compiled the largest ever registry of incident cases of pulmonary hypertension (PH) across the whole spectrum of the disease (ASPIRE – currently in submission). We have also published on the management and outcomes of pregnancy in PH and together with strand 2 have published on the diagnostic utility of both CT and MR in PH associated with systemic sclerosis. This work has been supported by unrestricted grants from the pharmaceutical industry (Actelion), which have funded 3 research fellows. During the last 2 years we have developed a large biorepository for the collection of samples from incident, treatment-naive patients. This provides a unique resource allowing us to look for changes in biomarkers or gene expression during disease progression and determine the effect of treatment, in conjunction with Dr Allan Lawrie (MRC Career Development Award Fellow -Strand 3). This biorepository has been funded by the NIHR Cardiovascular Biomedical Research Unit. Strand 2 has involved work on the role of imaging, particularly MRI, in the assessment of PH, in conjunction with the University Academic Unit of Radiology (Professor J Wild). Research has focussed on the effects of PH on the right ventricle, pulmonary arterial flow, lung perfusion, structural changes related to interstitial lung disease. We have published on the diagnostic utility of both CT and MR in PH associated with systemic sclerosis. A novel assessment of oxygen uptake and V/Q matching in CTEPH using hyperpolarised Helium-MRI has begun. This work has been taken forward with the help of two BMedSci students (Dan Hagger, Adam Telfer) and two radiology research fellows (Andy Swift PhD, Smitha Rajaram MD), jointly supervised by David Kiely and Jim Wild, and a part funded MRI-physicist (Helen Marshall). As well as the afore-mentioned papers in the radiological assessment of systemic sclerosis-associated PH several papers are currently in submission looking at novel cardiac parameters and novel ways of assessing parenchyma and PE using MR. This work has also been funded by the pharmaceutical industry (Bayer and Pfizer), with additional funding from the CV BRU and EPSRC. Strand 4: During the last 5 years we have recruited patients to several multi-centre large randomised controlled trials including IMPRES – imatininb, FREEDOM C – oral treprostinil, COMPASS – oral combination therapy, VISION – combination oral/nebulised therapy, PATENT – riociguat, AMBITION – oral combination therapy. Collaborations across divisions with clinicians and cardiovascular scientists are also helping to develop new targets that might be important in the treatment of pulmonary hypertension. In particular, we are examining the roles of hormonal systems that control fluid balance and blood pressure in the development of pulmonary hypertension. We are also a leading contributor to early phase clinical and experimental medicine trials in PH, and aim to phenotype and study our large patient cohort to directly improve patient care over the next 5 years. 3. Interstitial Lung Disease We have developed a regional referral service for ILD, underpinned by a specialist MDT meeting, and have co-written the international guidelines for patient management (Thorax 2008). We are participating in 2 major MRC funded studies (Whyte co-app), the Trent Lung Fibrosis Network and the PROFILE Biomarker Study. Whyte is also a member of the UK Lung Fibrosis Network. We have also contributed patients for industry studies, with 2 further studies planned. We have a relevant basic science project determining the interplay between lung inflammation and fibrosis (funded by Wellcome Trust) that has identified a potential therapeutic target in IPF, a disease with no effective therapy and a very poor prognosis. Much of the basic science described in Theme 1 is also relevant to this Theme. 4. Occupational Lung Disease The occupational respiratory disease research theme is embedded within the Centre of Workplace Health (CWH), a tripartite relationship between the Health and Safety Laboratory, the University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust. The Centre has three strands of activity; (i) research into occupational respiratory disorders, (ii) provision of “strategic” occupational health services (such as occupational health needs assessments for industries) and (iii) teaching and training issues. CWH has funded a number of clinical research fellows, 2 currently completing higher degrees (Darby, Burton) and a further post currently advertised. HSE generic research issues, 5 years of strategy; this has largely been driven by the requirements of the major research funder in occupational respiratory ill health, the Health and Safety Executive (HSE). Indeed, the direction of research into occupational respiratory disorders was driven early on in this time period by government targets to reduce the incidence of occupational asthma specifically. In this regard, our research strategy was to engage with HSE to formulate studies and research ideas that would lead to a reduction in occupational asthma. Examples of such work include the routes of referral study, diagnostic agreement of occupational asthma and the development of a BTS standard of care for occupational asthma. HSE specific issues; certain focused requirements have also been researched, and include case definitions for occupational extrinsic allergic alveolitis, a large population study of COPD has been carried out to better define the size of the population attributable fraction for COPD of relating to harmful inhaled workplace exposures. Additional work has taken place to assess health surveillance approaches, including the development of a position paper on beryllium-exposed workers. Clinical issues; whilst the Centre for Workplace Health only has currently a limited capability to carry out clinical research, as no job planned time is set aside for such work at consultant level, there is a study currently running that relates to the use of exhaled nitric oxide in the assessment of patients being assessed for possible occupational asthma. The primary target for respiratory research monies is HSE. Other providers will be targeted as required, although further work with BOHRF is anticipated. NIHR portfolio status is not granted to HSE funded studies currently. 5. Infection and Immunity Sheffield hosts the regional centre for cystic fibrosis (F. Edenborough, M. Wildman) and there is also a specialist service in bronchiectasis and lung infection (O. Pirzada, S. Bianchi). A number of industry- funded studies are underway or have been completed. Dr Wildman is a member of the UK CF Registry Steering group and is currently working with this group to develop case mix adjustment measures for the national registry. He has also carried out some epidemiological comparisons of US and UK CF data using routine data. There is ongoing work within the CF unit to investigate objective measures of adherence and this is linked with work to classify patients by stage of change in regard to adherence behaviours. There are several, active clinical studies recruiting within STH and offering patients further therapy for Bronchiectasis. Both portfolio and non-portfolio research work is included with new anti-inflammatory studies planned to start this year. STH is collaborating with other centres at an exciting time for Bronchiectasis and lung inflammation, working with several other centres in the newly formed Northern Bronchiectasis Research group to help co-ordinate local and multicentre- bronchiectasis related research. Much of the basic science described in Theme 1 is relevant to lung infection and applicable in this area. 6. Ventilation The Sheffield Thoracic Assisted Respiration and Sleep Service is operated by Drs Bianchi and Hughes. It offers specialist management of conditions such as obstructive sleep apnoea and has a regional commitment to the management of patients with chronic respiratory failure. Dr Hughes specialises in the acute and chronic management of respiratory failure secondary to COPD while Dr Bianchi has developed a service in non-invasive ventilation focussing on chronic respiratory failure secondary to thoracic cage deformity, diaphragmatic weakness and neuromuscular disease. Several areas of research have been developed focussing on the management of patients with chronic neuromuscular weakness (particularly motor neurone disease), in patients with central sleep apnoea related to cardiac failure and assessing the physical, neurocognitive and microvascular effects and consequences of OSA and the therapeutic effects of CPAP. Additional Information Although not recorded as Respiratory Research Activity it should be noted that the Lung Cancer service, led by Dr Jennifer Hill, recruits large numbers of patients to lung cancer trials based in Weston Park. Indeed, Sheffield is one of the top recruiting centres in the national lung cancer network. We have a major and increasing emphasis on experimental medicine research directly studying the human. We have two principal core experimental medicine themes within respiratory medicine, pulmonary inflammation and pulmonary hypertension. We undertake internationally recognized research into airway inflammation, neutrophil and macrophage biology and host pathogen interactions. This work has been supported by 2 MRC and 1 Wellcome Senior Clinical Fellowship and we have substantial current MRC funding. We have recently become a lead centre in the MRC/ABPI COPD Consortium, a £7M initiative across 10 centres. Research Strategy 2011-2016 For each theme, please describe your research strategy for the forthcoming five years, again indicating direction, detail and funders. 1. Airways Disease The theme has extensive strengths, but is facing significant challenges, with the changes to research funding underway nationally. The strengths of the theme lie in its world-class research on mechanisms of host-pathogen interactions in the airways. The theme will clearly continue to drive the highest possible quality research in this area. Key targets will be the ongoing development of translational themes (such as Prof Sabroe’s human challenge model), as well as developing the translational research opportunities arising from the MRC/ABPI COPD Consortium, a key national initiative bringing significant funding. The aims of the Theme will be to uncover how pathogens cause inflammation of the airways, develop new targets that might be feasible treatment points for airways inflammation, and develop research on existing targets and new therapeutics already underway in the group. This work will enhance partnerships with Pharma (several discussions re add-on studies to the MRC/ABPI initiative are underway). Dr Sarah Walmsley will be supported for an application for a Senior Clinical Fellowship (Wellcome or MRC), for which she should be very competitive. Ongoing strategic thought is needed to maximise the research opportunities of the senior clinical team. Prof Sabroe has moved from a 80:20 research:clinical commitment to a 50:50 job plan, which reduces his maximum feasible input into strategic research. He is likely to apply for a Wellcome Senior Investigator Award or ERC Advanced Fellowship, and will require significant support to write these applications. Dr Renshaw will complete his Senior Fellowship in 2013, and if his substantial expertise is to be retained, a suitable post will need to be constructed enabling support of his ongoing research. Dr Lawson/Pro Wild will continue to develop MRI imaging applications for COPD, e.g. in monitoring treatment responses and as an intermediate phenotype of disease progression (advanced industry interest in funding this area). Dr Lawson will also pursue further funding to investigate the role of inspiratory muscle training in COPD. He has a number of clinical studies ongoing/due to start (Boehringer Ingelheim/Pfizer). 2. Pulmonary Vascular Disease. Strand 1 Detailed Clinical Phenotype and Bioresource: Continued expansion of the biorepository, with additional funding being sought post BRU. Formation of a tissue biobank – a unique endeavour to obtain post-mortem tissue from patients (Prof Sabroe). Ethics approval has been granted. Initial pilot funding may be available from CVBRU funds with a view to obtaining longer-term funding from a larger funding body. Our next research fellow will focus on systemic sclerosis-associated PH and this work will involve both strand 2 and 3. They will focus on different groups of patients with systemic sclerosis (PH +/-, ILD +/-. TLCO preserved or reduced) and will assess the use of novel radiological parameters (hyperpolarised Helium and Xenon, perfusion time to peak) as well as genomics in tightly phenotyped patients from each of these groups (funding – hopefully industry for initial funding of fellow with view to a grant proposal (Arthritis Research UK)). We are also planning to start recruitment later this year into a portfolio study of intravenous iron in idiopathic pulmonary arterial hypertension (PAH) in conjunction with Hammersmith and Papworth (BHF grant and CLRN funds). A further collaborative RCT (with Hammersmith hospital) of a novel agent (DCA) is also planned. Strand 2 Pulmonary and Cardiac Functional Imaging: Our present 2 MD students will complete their studies into novel MR parameters of pulmonary vascular function and disease. A pre and post therapy study is planned for late 2011. An MRI investigation into the RH and LH interaction in LH PH is planned for 2011 led by Andy Swift with Cardiology (Dr. Alli Morton). To fully investigate MR as an evaluation of therapy in PH a large two centre NIHR HTA or EME proposal is planned which will be led by Sheffield in collaboration with Papworth. A study of hyperpolarised 129Xe MRI as a probe of interstitial thickening and gas transfer in systemic sclerosis associated PH is planned for late 2011-2012. In conjunction with Professor Rod Hose (Medical Physics) we plan to use of anatomical and physiological sensitive measures from MRI and clinical tests as the basis for boundary conditions and validation endpoints in multi-scale models of the pulmonary venous system and for patient specific geometry. Funding for an EPSRC PhD student co-supervised by Wild and Hose has been secured to take this image based modelling forward and it is planned to apply for European or EPSRC funding for this collaboration. Strand 3 Pre-clinical models and discovery science: Work on novel pathways TRAIL, OPG and IL-1 in PH will continue (Dr Lawrie) and it is hoped that phase 1 and 2 studies targeting this pathways will result (funding- MRC). Drawing on the expertise in inflammation of Professor Sabroe, Professor Whyte and Dr Walmsley the role of HIF pathways and neutrophil function in PH and especially the interaction with iron metabolism will be explored. Strand 4 Industry-sponsored clinical trials: Enrolment into current active studies will continue (PATENT, AMBITION, COMPASS) while patients will continue to be followed in extension arms of completed RCTs (FREEDOM, Tadalafil). 3. Interstitial Lung Disease 1. Continue recruiting to the MRC-funded portfolio-adopted studies, whilst preparing future grant applications based on preliminary biomarker studies – Whyte/Bianchi 2. Explore translational potential of basic science findings with regard to the TRAIL death ligand to a “first in man” study - Whyte 3. Develop novel MRI imaging techniques (3He and 129Xe) to explore V/Q mismatching in ILD, together with novel applications for assessment of regional lung hypoxia Wild/Whyte/Walmsley, building to a Clinical Fellowship application (Zhe Hoo, ACF in Respiratory Medicine) 4. Play a significant role in UK Lung Fibrosis Network applications to NIHR/MRC for multi-centre studies 4. Occupational Lung Disease Current national research strategy into occupational lung disorders is being formulated and discussed by the GORDS group, the Group of Occupational Respiratory Disease Specialists. CWH will play a part in formulating this strategy. HSE generic issues; it is likely that our research strategy will align with HSE’s needs and also take into any formulated GORDS view. The current priority research areas summarised by GORDS are as follows; Occupational COPD, causation and interventions Occupational asthma interventions and redeployment Occupational extrinsic allergic alveolitis 5. Infection and Immunity Infection and Immunity will benefit from a prospective database that is planned within the department. Drs Edenborough and Bianchi attend the Northern Bronchiectasis research group which is performing a Delphi study to identify areas of research for collaboration across the region. The portfolio of industry studies and collaboration with the Clinical Research Facility will continue to expand. CF is currently undergoing a major service improvement project (led by M. Wildman) with microsystems analysis in collaboration with the CF Trust, the North American CF Foundation and Dartmouth University with grant applications in preparation. This unpacking and optimisation of the clinical management of CF is determined to identify what elements of treatment matter to patients, optimising adherence using motivational interviewing techniques and changing the service infrastructure from being reactive (dealing with infection and weight loss) to prevention in a more structured way including telemedicine, emonitoring and feedback from logging devices. 6. Ventilation The research programme for sleep & ventilation, while in its infancy, is expanding through greater involvement in national studies and through expansion of local projects. To date we have explored the effect of CPAP therapy in moderate/severe OSA in terms of effect on exercise ability and are nearing completion of a lifestyle intervention/motivational interviewing intervention study capitalising in improvements in exercise ability. We plan to explore mechanisms of effect through cross sectional studies and through analysis of blood biomarkers and changes in microvascular function. We aim to expand these studies through a multicentre approach utilising telemedicine as a modality of therapy delivery. Furthermore early studies have been conducted exploring the physical and neurocognitive consequences of sleep deprivation in late pregnancy and secondary to sleep apnoea. Dr Bianchi is collaborating with The University of Sheffield Psychology Department in exploring consequences and beliefs regarding sleep deprivation in new mothers. The group are key members of a national consortium proposing a large NIHR study (SAVE) exploring the effect of CPAP therapy on cardiovascular outcomes in patients with cardiovascular and cerebrovascular disease with previously undiagnosed or mildly symptomatic OSA. In patients with severe congestive cardiac failure we are a recruiting site for the international SERVE-HF study exploring the use of autoservoventilation in patients with consequent central sleep apnoea or Cheyne-Stokes Respiration. Dr Bianchi is a co-investigator in a number of collaborative studies with the department of neurology exploring aspects of care related to NIV in MND. A study exploring the role of cough- assist devices for enhanced sputum clearance in patients commencing NIV is in progress, as is a study exploring patient and carer experience of the NIV initiation and management process following the development of respiratory failure. Furthermore, studies exploring mechanisms of early detection of respiratory failure and validation studies of transcutaneous CO2 monitoring are ongoing. The group are about to start recruitment to the NIHR funded DiPALS Trial, and multicentre UK study of diaphragmatic pacing in MND patients with respiratory failure. Dr Hughes has developed a research programme within the Respiratory Support Unit exploring the use of transcutaneous carbon dioxide monitoring against arterial blood gas analysis (the currently accepted gold standard). Specific Targets 2011-2012 Finally, for each theme, please identify in detail the specific targets you hope to meet during the next 12 months. Please indicate the projects you expect to develop, the funding bodies to which you will be applying, and the projects and funding involved, naming the lead researcher in each case. 1. Airways Disease 1. Application to Wellcome Trust and MRC for a Senior Clinical Fellowship (Sarah Walmsley) 2. Application to continue the MRC/ABPI COPD consortium, with additional industry applications (Whyte/Dockrell/Sabroe). 3. Successful publications of key studies of new human models of inflammation (Sabroe), recently funded for further development by Heart Research UK. 4. Exploitation of novel data in neutrophil biology to generate key publications (Sabroe/ Whyte) and apply for further MRC funding 5. Completion of GSK-funded MRI imaging study in COPD (Lawson/Wild) 2. Pulmonary Vascular Disease Strand 1 Detailed Clinical Phenotype and Bioresource. i. Biorepository (Kiely) – obtain funding (CVBRU/other) for continued sample collection ii. Tissue Bank (Sabroe) – obtain pilot funding (CVBRU/other) and commence recruitment iii. Clinical Research Fellow (Kiely) – obtain initial funding (industry) and commence post leading to grant proposal to Arthritis Research UK. iv. Ferrinject study (Kiely) – commence recruitment (BHF/CLRN) v. DCA study (Kiely) – commence recruitment vi. Develop clinical trial of aldosterone antagonist (Sabroe/Condliffe) – funding stream tbc Strand 2 Lung and Cardiac Functional Imaging. i. Novel MR parameters (Wild/Kiely/Condliffe/Elliot/Swift) – Finish current work and several publications. Plan application to HTA for NIHR funding to help establish high throughput of PH and PE MRI research scans and fund future clinical fellows, MRI physicist and research radiographer. ii. Hyperpolarised gas MRI (Wild/Elliot/Condliffe/Kiely) – Finish pilot 3He study and publish. Commence 129Xe study in SS PH (Wild/Kiely/Condliffe/Elliot). iii. Computational modelling (Wild/Hose/Kiely/Clayton/Lawrie). Recruit PhD student physicist/mathematician. Use data for pilot for large image based modelling grant with potential preclinical imaging and modelling component. Strand 3 Pre-clinical models and discovery science: i. Develop clinical trial of IL-1 based therapy (Lawrie) – funding stream tbc 3. Interstitial Lung Disease 1. Significant recruitment to the MRC-funded Trent Lung Fibrosis and PROFILE studies - Whyte/Bianchi 2. Explore possibility of a TRAIL “first in man” study - Whyte 3. Obtain ethics approval then pilot data for 3He/129Xe MRI imaging in ILD 4. Occupational Lung Disease 1. Further development of GORDS related research (David Fishwick, Chris Barber) 2. Further development of occupational COPD work in collaboration with Imperial College (David Fishwick) 3. Further development of a standard of care with the BTS, for workers with COPD (David Fishwick) 4. Further development of metal working fluid alveolitis case definitions (Chris Barber) 5. Further development of silica and foundry work (Chris Barber and David Fishwick) 5. Infection and Immunity 1. CF microsystems analysis, Dr M Wildman; 1 year project , application to, specific goals 2. CF electronic patient record, Dr F Edenborough; collaboration with Leeds and EMIS, conversion to full EPR using trend analysis tools and to feed into 1 above. No specific grant applications at this stage but considerable overlap with funding strategies in 1 above. 6. Sleep & Ventilation 1. Complete BMedSci, MPhil and PhD student projects and submit papers for publication 2. Continue/commence recruitment to NIHR studies 3. Seek funding for microvascular studies and prepare telemedicine/multicentre protocols for ethical clearance and funding applications (NIHR) Infrastructure Requirements To fulfil your ambitions you will be expecting to rely on the provision of central services and facilities. To help with the planning of this provision, please identify for each of your themes your expectations of the core facilities required to allow you to deliver your outputs. These might include laboratory, imaging and pharmacy facilities, CRF availability, research nursing staff, advisory staff etc. Timetabled quantification will be particularly helpful. There are some important generic issues for Respiratory Medicine: 1. A general paucity of research support in Respiratory Medicine, in terms of dedicated research nurses and admin/clerical support. We have been allocated 1 day per week of an excellent research co-ordinator but clearing ISR/ethics/R&D hurdles is undoubtedly limiting our rate of progress. 2. Provision of sample storage/biobanking in the post-BRU era. 3. The current lack of any patient database to facilitate patient recruitment to studies. 4. The requirement for ongoing respiratory physiology and bronchoscopy on the RHH site. Many specialist clinics are held at the RHH site with patients attending who may be suitable for research (PH/ILD/COPD/Asthma/OLD). 5. Radiology support is critical for lung disease research. Specific issues with regard to MRI are discussed below but CT scanning also essential. 6. We are dependent upon CRF support for our Portfolio-funded studies 7. Pharmacy support is essential for a number of the studies described. Issues raised by Themes include: Airways Disease 1. Reduced consultant time available for research as external Fellowships expire 2. Availability of research PET scanning could greatly enhance translation of novel observations Pulmonary Vascular Disease 1. Research nurse support for continued recruitment of the PH Bioresource 2. CRF/Research nursing staff support for Ferrinject study (will be a Portfolio Study) 3. Assurance of patient throughput for clinical and research MRI scans and interaction with NHS radiology management, upon which all of Strand 2 depends 4. Continuation of the tissue biorepository and sample storage facilities currently supported by the BRUs Interstitial Lung Disease 1. Lack of patient database for tracking of patients with rarer lung diseases 2. Concerns about imaging pipeline as above 3. Desirability of a biobank resource for some of these patient groups Occupational Lung Disease The core facilities within CWH are based at the Health and Safety Laboratory in Buxton. The latter is an agency of HSE, and represents a state of the art laboratory facility. All research work commissioned by HSE, with few exceptions, are carried out at this site. In order to maximise our clinical research, the following core facilities would be a requirement; 1. Access to a respiratory physiology laboratory, with a specific and non-specific challenge facility; this is currently present at RHH. Support from a part time respiratory physiologist would greatly assist new study development (within 1 year) 2. Access to a searchable research style database to identify suitable research patients with occupational respiratory diseases (within 1 year) 3. Access to a research database to allow inclusion of consenting NHS patients to be enrolled in clinical research, and to allow assessment of group data (for example quality control studies, cohort studies), (within 1 year). 4. Access to database expertise for epidemiological studies. 5. Access to immunology laboratory facilities that can assess simple and complex immunology relevant to occupational sensitisation (IgE, IgG, flow cytometric facilities) Sleep & Ventilation Research within the sleep service has been, and remains, significantly compromised due to the high clinical burden, lack of dedicated research staff and space/equipment. To date, therefore, studies have been conducted by students undertaking brief research projects and have taken sole ownership of the entire project reducing time burden on respiratory physiology staff. Attempts to more closely involve physiologists have been confounded by clinical workload and cross-site working to the extent that studies have failed to recruit. Alternatively, for larger studies, research staff from the CRF have been utilised to good effect (but at substantial additional cost). Access to a research database would additionally be of substantial benefit. Little time is available within consultants working plans to deliver high quality research.
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