Investigation into the role of ceramide in the pathogenesis of cystic fibrosis lung disease
Lead Research Organisation:
Newcastle University
Department Name: Translational and Clinical Res Institute
Abstract
Cystic fibrosis (CF) is the most common life-limiting inherited disease in the United Kingdom (UK). Over 9,000 people have CF and it affects around 1 in 2,500 newborn babies. CF is a chronic condition that is associated with significant medical problems that occur from an early age and may present at birth. Living with CF necessitates a daily burden of treatment, including oral medications, nebulisers, physiotherapy and a special diet, plus frequent clinic visits and prolonged hospital admissions.
Progressive lung disease is the most important problem in CF and regularly leads to premature death in young adulthood. The median life expectancy for people with CF in the UK is 34 years. Although we know that CF is a condition that is inherited and involves problems with an ion channel in cells the exact cause of the lung disease is not fully understood. Current treatments do not cure patients, all of whom get progressive complications, most notably recurrent lung infections and inflammation leading to gradual loss of lung function and ultimately respiratory failure. Many patients require assessment for lung transplantation although this is not a viable option for everyone and there is a severe shortage of donor organs.
A major problem with CF research is that it has traditionally been difficult to obtain highly relevant cells from inside the lungs of people with CF. My previous work performed during my PhD funded by a Medical Research Council (MRC) and CF Trust Training Fellowship identified a reliable way to do this by growing the cells directly from the diseased lungs removed when people with CF undergo lung transplantation at the Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne. I was also able to collect lung tissue for a research archive during this work.
Recently researchers have found increased levels of a fat called 'ceramide' in lung tissue from a CF mouse model. This accumulation was associated with lung infection and inflammation - as we see in people with CF. In this current project I aim to use the valuable human CF cells and tissue to measure the levels of ceramide present. I will then investigate why ceramide may accumulate in CF cells, how it may cause lung inflammation and importantly a potential novel treatment to try and reduce ceramide levels.
I will visit and collaborate with centres of excellence in Cambridge, Paris, Essen and New York to perform this work and will bring back knowledge and experience gained in these centres to further develop research in Newcastle.
Progressive lung disease is the most important problem in CF and regularly leads to premature death in young adulthood. The median life expectancy for people with CF in the UK is 34 years. Although we know that CF is a condition that is inherited and involves problems with an ion channel in cells the exact cause of the lung disease is not fully understood. Current treatments do not cure patients, all of whom get progressive complications, most notably recurrent lung infections and inflammation leading to gradual loss of lung function and ultimately respiratory failure. Many patients require assessment for lung transplantation although this is not a viable option for everyone and there is a severe shortage of donor organs.
A major problem with CF research is that it has traditionally been difficult to obtain highly relevant cells from inside the lungs of people with CF. My previous work performed during my PhD funded by a Medical Research Council (MRC) and CF Trust Training Fellowship identified a reliable way to do this by growing the cells directly from the diseased lungs removed when people with CF undergo lung transplantation at the Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne. I was also able to collect lung tissue for a research archive during this work.
Recently researchers have found increased levels of a fat called 'ceramide' in lung tissue from a CF mouse model. This accumulation was associated with lung infection and inflammation - as we see in people with CF. In this current project I aim to use the valuable human CF cells and tissue to measure the levels of ceramide present. I will then investigate why ceramide may accumulate in CF cells, how it may cause lung inflammation and importantly a potential novel treatment to try and reduce ceramide levels.
I will visit and collaborate with centres of excellence in Cambridge, Paris, Essen and New York to perform this work and will bring back knowledge and experience gained in these centres to further develop research in Newcastle.
Technical Summary
Cystic fibrosis (CF) is the most common genetically acquired life-limiting disorder in the UK. Lung disease is responsible for over 95% of morbidity and mortality, the exact pathogenesis of which remains poorly understood. There is an acute need for the development of novel therapeutic approaches.
Raised levels of the sphingolipid ceramide have been described in a CF mouse model that are associated with lung inflammation, a key feature of human CF lung disease. In this Clinician Scientist Fellowship proposal I will combine primary bronchial epithelial cells and human CF lung tissue with the latest mass spectrometry techniques to accurately measure and image ceramide in the airway epithelium. I will then examine a potential mechanism whereby ceramide may accumulate in the plasma membrane due to reduced acid ceramidase activity and cause inflammation. I hypothesise that ceramide accumulates in microdomains of the plasma membrane in CF airway epithelial cells that causes NADPH oxidase to cluster resulting in raised production of reactive oxygen species, increased production of inflammatory mediators and airway inflammation. I will also examine whether the altered ceramide metabolism is associated specifically with defective CF transmembrane regulator function (CFTR). Finally I will investigate the potential therapeutic use of recombinant acid ceramidase in models of CF lung disease to reverse the accumulation of ceramide and reduce airway inflammation.
This fellowship will advance knowledge, improve methodology and answer key questions that may support ceramide metabolism as a potential novel therapeutic avenue for CF lung disease including the use of recombinant acid ceramidase.
Raised levels of the sphingolipid ceramide have been described in a CF mouse model that are associated with lung inflammation, a key feature of human CF lung disease. In this Clinician Scientist Fellowship proposal I will combine primary bronchial epithelial cells and human CF lung tissue with the latest mass spectrometry techniques to accurately measure and image ceramide in the airway epithelium. I will then examine a potential mechanism whereby ceramide may accumulate in the plasma membrane due to reduced acid ceramidase activity and cause inflammation. I hypothesise that ceramide accumulates in microdomains of the plasma membrane in CF airway epithelial cells that causes NADPH oxidase to cluster resulting in raised production of reactive oxygen species, increased production of inflammatory mediators and airway inflammation. I will also examine whether the altered ceramide metabolism is associated specifically with defective CF transmembrane regulator function (CFTR). Finally I will investigate the potential therapeutic use of recombinant acid ceramidase in models of CF lung disease to reverse the accumulation of ceramide and reduce airway inflammation.
This fellowship will advance knowledge, improve methodology and answer key questions that may support ceramide metabolism as a potential novel therapeutic avenue for CF lung disease including the use of recombinant acid ceramidase.
Planned Impact
BACKGROUND
Cystic fibrosis (CF) is the most common life-limiting genetically acquired disorder in the UK. Lung disease is responsible for over 95% of morbidity and mortality, the exact pathogenesis of which remains poorly understood, and ultimately leads to respiratory failure in young adulthood. Living with CF necessitates a heavy and life-long burden of care. It follows that there is an urgent need to improve understanding of pathogenesis and develop novel therapeutic strategies.
BENEFITS TO HEALTH
Patients, carers and families: The work in this fellowship will increase understanding of the mechanisms involved in CF lung disease and provide information on ceramide metabolism as a potential new therapeutic avenue. I will specifically explore if treatment with recombinant acid ceramidase may reverse the accumulation of ceramide in models of CF.
Wider benefits to the NHS and healthcare research: Data generated in this fellowship will inform future research directions including refinement of approaches to pharmacological manipulation of sphingolipid metabolism. The development of technologies to accurately measure sphingolipids in primary airway epithelial cells and to image lipids in human lung tissue will represent an important improvement in the methodology currently used to study sphingolipid biology. Abnormalities in sphingolipid metabolism have been identified in a number of other lung diseases and these approaches are likely to be of benefit beyond CF including emphysema and asthma. The fellowship will also provide support for the ongoing utilisation of explanted CF lung tissue at one of the largest lung transplantation centres in Europe. The importance and scarcity of primary tissue and cells is widely recognised by the CF research community and there is a clear intention to continue active collaboration with researchers nationally and internationally along with ongoing dissemination of the culture techniques. The value of such a resource is exemplified by the recent development of ivacaftor, which was validated in primary cells prior to successful translation.
ECONOMIC BENEFIT
In addition to potential economic benefits to the NHS the development of novel techniques to accurately measure and image ceramde in primary cells and lung tissue are likely to generate further research and drug development income to the UK and European Union. The post-doctoral research assistant employed as part of the fellowship will acquire transferable skills equally relevant to a future career in academia or the pharmaceutical industry.
CHANGE IN POLICY
Through prompt communication to a broad range of researchers, clinicians and health care professionals at large national and international meetings and in open access peer- reviewed journals the results of the research will be widely disseminated to key decision and policy makers. This will be complemented by a strong policy of engagement with
influential patient groups such as the CF Trust.
Reference:
[1] Ramsey et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663-1672
Cystic fibrosis (CF) is the most common life-limiting genetically acquired disorder in the UK. Lung disease is responsible for over 95% of morbidity and mortality, the exact pathogenesis of which remains poorly understood, and ultimately leads to respiratory failure in young adulthood. Living with CF necessitates a heavy and life-long burden of care. It follows that there is an urgent need to improve understanding of pathogenesis and develop novel therapeutic strategies.
BENEFITS TO HEALTH
Patients, carers and families: The work in this fellowship will increase understanding of the mechanisms involved in CF lung disease and provide information on ceramide metabolism as a potential new therapeutic avenue. I will specifically explore if treatment with recombinant acid ceramidase may reverse the accumulation of ceramide in models of CF.
Wider benefits to the NHS and healthcare research: Data generated in this fellowship will inform future research directions including refinement of approaches to pharmacological manipulation of sphingolipid metabolism. The development of technologies to accurately measure sphingolipids in primary airway epithelial cells and to image lipids in human lung tissue will represent an important improvement in the methodology currently used to study sphingolipid biology. Abnormalities in sphingolipid metabolism have been identified in a number of other lung diseases and these approaches are likely to be of benefit beyond CF including emphysema and asthma. The fellowship will also provide support for the ongoing utilisation of explanted CF lung tissue at one of the largest lung transplantation centres in Europe. The importance and scarcity of primary tissue and cells is widely recognised by the CF research community and there is a clear intention to continue active collaboration with researchers nationally and internationally along with ongoing dissemination of the culture techniques. The value of such a resource is exemplified by the recent development of ivacaftor, which was validated in primary cells prior to successful translation.
ECONOMIC BENEFIT
In addition to potential economic benefits to the NHS the development of novel techniques to accurately measure and image ceramde in primary cells and lung tissue are likely to generate further research and drug development income to the UK and European Union. The post-doctoral research assistant employed as part of the fellowship will acquire transferable skills equally relevant to a future career in academia or the pharmaceutical industry.
CHANGE IN POLICY
Through prompt communication to a broad range of researchers, clinicians and health care professionals at large national and international meetings and in open access peer- reviewed journals the results of the research will be widely disseminated to key decision and policy makers. This will be complemented by a strong policy of engagement with
influential patient groups such as the CF Trust.
Reference:
[1] Ramsey et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663-1672
People |
ORCID iD |
| Malcolm Brodlie (Principal Investigator / Fellow) |
Publications
Zeybel G
(2017)
Ivacaftor and symptoms of extra-oesophageal reflux in patients with cystic fibrosis and G551D mutation
in Journal of Cystic Fibrosis
Zainal Abidin N
(2017)
Ataluren in cystic fibrosis: development, clinical studies and where are we now?
in Expert opinion on pharmacotherapy
Tissot A
(2018)
NonTuberculous Mycobacteria infection and lung transplantation in cystic fibrosis: a worldwide survey of clinical practice.
in BMC pulmonary medicine
Simpson K
(2017)
How to use nasal nitric oxide in a child with suspected primary ciliary dyskinesia.
in Archives of disease in childhood. Education and practice edition
Shakir S
(2022)
Elexacaftor-Tezacaftor-Ivacaftor improve Gastro-Oesophageal reflux and Sinonasal symptoms in advanced cystic fibrosis
in Journal of Cystic Fibrosis
Scott A
(2017)
Characterisation of eppin function: expression and activity in the lung.
in The European respiratory journal
Saint-Criq V
(2019)
Real-Time, Semi-Automated Fluorescent Measurement of the Airway Surface Liquid pH of Primary Human Airway Epithelial Cells.
in Journal of visualized experiments : JoVE
Saint GL
(2022)
Treating nontuberculous mycobacteria in children with cystic fibrosis: a multicentre retrospective study.
in Archives of disease in childhood
Robertson N
(2017)
Congenital Lung Agenesis: Incidence and Outcome in the North of England.
in Birth defects research
Roberts J
(2020)
Pediatric tracheostomy: A large single-center experience.
in The Laryngoscope
Roberts J
(2018)
A review of adenotonsillar hypertrophy and adenotonsillectomy in children after solid organ transplantation.
in International journal of pediatric otorhinolaryngology
Preece CL
(2016)
A novel culture medium for isolation of rapidly-growing mycobacteria from the sputum of patients with cystic fibrosis.
in Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Powell J
(2021)
Tracheostomy trends in paediatric intensive care.
in Archives of disease in childhood
Lin J
(2021)
Acute cigarette smoke or extract exposure rapidly activates TRPA1-mediated calcium influx in primary human airway smooth muscle cells.
in Scientific reports
Liew Z
(2017)
Successful outcome following pneumonectomy in a teenage boy with cystic fibrosis: a case report.
in BMC pulmonary medicine
Liew Z
(2020)
Physiological effects of high-flow nasal cannula therapy in preterm infants.
in Archives of disease in childhood. Fetal and neonatal edition
Jackson RM
(2022)
Conjunctival epithelial cells resist productive SARS-CoV-2 infection.
in Stem cell reports
Ibrahim S
(2017)
CK2 is a key regulator of SLC4A2-mediated Cl-/HCO3 - exchange in human airway epithelia
in Pflügers Archiv - European Journal of Physiology
Hatton C
(2021)
Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2
in Nature Communications
Harris CA
(2021)
Successful biodegradable stent insertion in an infant with severe bronchomalacia and cystic fibrosis.
in Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Haq IJ
(2021)
Clinical and molecular characterization of the R751L-CFTR mutation.
in American journal of physiology. Lung cellular and molecular physiology
Haq IJ
(2016)
A multifunctional bispecific antibody against Pseudomonas aeruginosa as a potential therapeutic strategy.
in Annals of translational medicine
Haq IJ
(2016)
Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets.
in Thorax
Haq I
(2017)
Should we use montelukast in wheezy children?
in Archives of disease in childhood
Haq I
(2019)
Modulator therapies for cystic fibrosis
in Paediatrics and Child Health
Haq I
(2022)
Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis.
in Pharmacogenomics and personalized medicine
Grudzinska FS
(2020)
Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age.
in Thorax
Grassmé H
(2017)
ß1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections.
in Cell host & microbe
Gilchrist FJ
(2020)
Developing a core outcome set for children with protracted bacterial bronchitis.
in ERJ open research
Gardner AI
(2019)
Epidemiology of Nontuberculous Mycobacteria Infection in Children and Young People With Cystic Fibrosis: Analysis of UK Cystic Fibrosis Registry.
in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Gardner AI
(2020)
Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis.
in American journal of respiratory and critical care medicine
Gardner AI
(2021)
Interferon regulatory factor 8 regulates expression of acid ceramidase and infection susceptibility in cystic fibrosis.
in The Journal of biological chemistry
Faulkner AL
(2022)
Characterising the allergic profile of children with cystic fibrosis.
in Immunity, inflammation and disease
Edmondson C
(2022)
The feasibility of home monitoring of young people with cystic fibrosis: Results from CLIMB-CF.
in Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Chan CD
(2021)
Lung biopsy in children: when is it useful?
in Archives of disease in childhood
Calella P
(2018)
Cystic fibrosis, body composition, and health outcomes: a systematic review.
in Nutrition (Burbank, Los Angeles County, Calif.)
Calella P
(2019)
Tools and Methods Used for the Assessment of Body Composition in Patients With Cystic Fibrosis: A Systematic Review
in Nutrition in Clinical Practice
Calella P
(2018)
Association between body composition and pulmonary function in children and young people with cystic fibrosis.
in Nutrition (Burbank, Los Angeles County, Calif.)
Brodlie M
(2015)
Targeted therapies to improve CFTR function in cystic fibrosis.
in Genome medicine
Brodlie M
(2016)
Leukotriene receptor antagonists as maintenance or intermittent treatment in pre-school children with episodic viral wheeze.
in Paediatric respiratory reviews
Brodlie M
(2015)
Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children.
in The Cochrane database of systematic reviews
Brodlie M
(2015)
Bile acid aspiration in people with cystic fibrosis before and after lung transplantation.
in The European respiratory journal
Becker KA
(2018)
Sphingolipids as targets for inhalation treatment of cystic fibrosis.
in Advanced drug delivery reviews
Bayes HK
(2016)
IL-22 exacerbates weight loss in a murine model of chronic pulmonary Pseudomonas aeruginosa infection.
in Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Bain R
(2021)
Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.
in Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Altmann T
(2018)
Endothelial cell damage in idiopathic pneumonia syndrome.
in Bone marrow transplantation
Al-Momani H
(2022)
Exposure to bile and gastric juice can impact the aerodigestive microbiome in people with cystic fibrosis.
in Scientific reports
Al-Momani H
(2017)
Nontuberculous mycobacteria in gastrostomy fed patients with cystic fibrosis.
in Scientific reports
| Description | Clinical Research Training Fellowship |
| Amount | £150,000 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2016 |
| End | 08/2018 |
| Description | Investigating the antimicrobial activity of sphingosine as a novel therapy against respiratory infection in children |
| Amount | £185,000 (GBP) |
| Organisation | Newcastle upon Tyne Hospitals NHS Charity |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2019 |
| End | 03/2021 |
| Description | MRC Confidence in Concept Award |
| Amount | £13,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2017 |
| End | 08/2018 |
| Description | Presentation to North East Young Person's Advisory Group |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Presentation by Clinical Research Fellow, Dr Iram Haq, to Young Person's Advisory Group, discussing paediatric respiratory research that is ongoing in the group and asking their opinion on research design, etc |
| Year(s) Of Engagement Activity | 2015 |