August 2013

Six Researchers from UCD Awarded Grants Through HRB Projects for Better Health

Thu, 22 August 13 06:57

Six researchers from UCD School of Medicine, UCD Conway Institute and UCD School of Public Health, Physiotherapy & Population Science have each been awarded HRB grants of up to €330,000, through the Projects for Better Health scheme.

According to Enda Connolly, Chief Executive at the HRB:

A total of 40 projects were selected from 209 applications. These were assessed by international peer review panels who believed the nature, scope and relevance of the proposals demonstrated great ambition and innovation that would lead to results that are relevant both nationally and internationally.

The projects are as follows:

Dr Patricia Fitzpatrick

Early evaluation of the clinical and economic effects of the Cystic Fibrosis Newborn Screening Programme

  • Dr Patricia Fitzpatrick
  • Senior Lecturer & Principal Investigator
  • School of Public Health, Physiotherapy & Population Science

This is a programme of research which addresses key outcomes in the newly established Cystic Fibrosis (CF) Newborn Screening programme. Ireland has the highest prevalence of CF in the world, with almost 3 cases per 10,000 of the population. Newborn screening for CF was introduced in 2011.

The study aims to evaluate important clinical and economic early parameters of the screening programme by comparing those children detected by the screening programme with children diagnosed after they present with symptoms in terms of the following: (i) health outcomes, including growth, weight and height, lung function, infection rates, number of admissions to hospital in the early years of life; (ii) timing of onset of early respiratory complications in children diagnosed through Newborn Screening; (iii) the effect of gender and presence of specific genes on early development of the disease; (iv) comparisons of screen-detected children’s early health with results from European and Australian CF registries; (v) health costs incurred by parents and by the health services, both prior to diagnosis and following diagnosis, including travel, time off work, GP and hospital visits, tests, hospital admissions and medications.

The proposed research on the CF Newborn Screening Programme will utilise both data collected by the National Cystic Fibrosis Registry and complementary additional data required for this very early evaluation.  An early follow-up evaluation of the Cystic Fibrosis Newborn Screening programme is both timely and necessary and will provide important information across clinical and economic parameters for this significant disease.

Dr Elizabeth Ryan

Understanding the link between molecular and microenvironmental influence on immunity in colorectal cancer

  • Dr Elizabeth Ryan
  • Senior Scientist & Principal Invesitgator 
  • UCD School of Medicine & Medical Science & St Vincent's University Hospital

Colorectal cancer is a major cause of cancer-related deaths in Ireland.  Approximately 2000 people are diagnosed in Ireland each year and the frequency of this cancer is increasing due to increasing numbers of aging people in our population. New and more effective drugs are being developed but we urgently need to develop better ways to classify these cancers so that patients receive the most appropriate and effective treatment for their tumour. Without this, patients may receive futile expensive treatments. These treatments have severe side-effects thus needlessly compromising the quality of life of the patients.

Over the last 20-30 years detailed molecular analyses of tumours have documented the genetic mutations associated with the development of colorectal cancer. These are actually limited to a few key genes that regulate very important events controlling growth of cells. However, this is only half of the picture – a tumour is composed not only of cancer cells but also infiltrating immune cells. Unfortunately as tumours grow these immune cells fail to kill the tumour. Instead the inflammation they cause fuels tumour growth by aiding the development of blood vessels that further sustain tumour expansion.

The goal of this project is to document the type of inflammatory environment that is associated with key genetic mutations in tumours. We have developed a method of culturing tumours in the lab that allows us to characterise their inflammatory environment. We will characterise both the genetic mutations underlying cancer pathogenesis and the inflammation that fuels tumour growth.

Ultimately, this will allow us to design treatment protocols that are 100 % specific for a patient’s tumour – taking both cancer cells and their environment into account.  

Dr Fionnuala Ní Áinle

Novel approaches to determining procoagulant state in early onset preeclampsia: diagnostic relevance and therapeutic opportunities

  • Dr Fionnuala Ní Áinle
  • Consultant Haematologist
  • UCD School of Medicine & Medicial Science & Mater Misericordiae University Hospital

Early onset preeclampsia is a disorder of pregnancy characterized by high blood pressure and protein in the urine. Mothers with this disorder may be very unwell and can die of their illness. Tragically, the number of mothers dying each year due to preeclampsia is equivalent to 170 jumbo jets of pregnant women. A quarter of the babies born to women with preeclampsia do not grow properly, and a third are born prematurely. Women with preeclampsia develop a poorly understood immune response, and are at significantly increased risk of blood clot formation. New data generated in our laboratory indicate that patients with early onset preeclampsia have an increased tendency to clot over and above that observed in healthy pregnant women.

Conversely, activated protein C (APC) is a blood protein that inhibits clotting. APC also inhibits inflammation and has been used as a therapy in patients with acute inflammatory conditions. Moreover, patients with severe preeclampsia may have reduced levels of protein C. Consequently, we hypothesize that APC may have potential as a novel therapy in preeclampsia.  We have recently developed novel APC molecules with greatly improved anti-inflammatory function. We plan to investigate the therapeutic potential of these APC molecules firstly in established animal models of preeclampsia.

In the clinical workstream of this project, we will combine analysis of clotting patterns in women with early onset preeclampsia with state-of-the-art ultrasound scanning, which can detect subtle abnormalities in fetal health at an early stage, and with maternal and fetal clinical outcome data, to better understand the role of dysregulation of coagulation in the pathogenesis of preeclampsia. This strategy has the potential to translate into more accurate prediction of disease severity in preeclampsia. By combining this with an investigation of a potential novel therapy, our vision is to enhance care provision for this high-risk group.

Professor Doug Veale

Redox regulation of angiogenesis and innate immunity in inflammatory arthritis

  • Professor Doug Veale
  • Professor of Medicine & Consultant Rheumatologist
  • UCD School of Medicine & Medical Science & St Vincent's University Hospital

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are the most common inflammatory arthritides (IA) affecting up to 2% of the population. Arthritis is a chronic and debilitating disease that impacts on a patients’ quality of life resulting in irreparable damage and lifelong functional impairment. Formation of new blood vessels is one of the initiating events in IAIA. Identifying the factors involved in regulating new blood vessel formation, that allows immune cells to migrate from the blood to invade the cartilage and bone is critical to understanding the processes involved in driving joint inflammation. In the joint of patients with IA the new blood vessels growth and increase the number of immune cells leads to low oxygen levels (hypoxia) in the joint. In this proposal we will investigate if a limited oxygen supply to the joint promotes formation of new blood vessels. We will also examine the role of the mitochondria (the cellular energy center) - in regulating inflammation in the joint. In particular, we will use cells lacking mitochondria to test whether hypoxia promotes progression of arthritis, through induction of a new blood vessel growth and activation of the inflammasome, a protein complex in cells that regulates key inflammatory mediators.

Targeted therapies inhibiting TNF have advanced the treatment of IA, however these novel treatments are expensive, placing further strain on an already over-stretched health budget, they are partially effective with but fail in up to 30% of patients. The specific focus of this project is to determine the link between new blood vessel formation, mitochondrial dysfunction, and the inflammasome using samples obtained from IA patients and to examine the effect of TNFi therapy. Furthermore, we aim to examine if anti-oxidant treatments may restore mitochondrial functions resulting in inhibition of pro-inflammatory processes such as new blood vessel formation and cell migration/activation.

Dr Breandan Kennedy

Developing Improved Therapeutics For Ocular Neovascularisation & Inflammation

  • Dr Breandan Kennedy
  • Senior Lecturer & Conway Fellow
  • UCD School of Biomolecular & Biomedical Research & UCD Conway Institute

Diabetic retinopathy, age-related macular degeneration and glaucoma are among the leading causes of human blindness. Hallmarks of these eye diseases include abnormal growth of new blood vessels (neovascularization), excessive build up of fluid (retinal/macular oedema) and inflammation. Therefore, the discovery and development of more effective drugs/combinations that optimally prevent unwanted new blood vessels forming, and that reduce swelling and inflammation in the eye can lead to better patient outcomes.

The most effective current therapy targeting unwanted, leaky blood vessels in the eye involves a monthly injection of a large antibody into the patient’s eye. This can be painful to the patient, increases risk of infection to the eye and is expensive in terms of the clinical time and drug costs. Thus, there is an unmet clinical need to develop novel and more cost-effective drugs which can be delivered in a more patient friendly manner and which still inhibit unwanted blood vessel growth, inflammation and swelling in the eye.

The Kennedy laboratory utilises an innovative method of identifying novel drugs that stop the development of new blood vessels using zebrafish, human cell lines and mouse models. We have assembled a team with proven expertise in uncovering novel drugs that inhibit blood vessel growth and developing these in pre-clinical models of blindness. In this project, we apply this critical human mass and our established technology platforms to identify novel, safe and effective drugs and/or drug combinations which prevent the growth of disease-associated blood vessel growth, inflammation and oedema. Ultimately, the output of this research will be novel drugs with potential to expand and enhance treatment options available to patients with angiogenesis- and inflammatory-related blindness. This has the potential to reduce the social and economic impact of blindness in Ireland. 

Dr Christine Costello

Lung selective dysregulation of the CXCR7/CXCL12 biological axis: a novel pathomechanism in human pulmonary vascular disease

  • Dr Christine Costello
  • College Lecturer & Senior Researcher
  • UCD School of Medicine & Medical Science & UCD Conway Institute

Chronic lung diseases including asthma, cystic fibrosis and occupational lung diseases are amongst the commonest causes of death and disability worldwide.  In Ireland, respiratory diseases impose a particularly heavy burden; Ireland has the highest death rate from respiratory disease in western Europe.  Faced with this large and increasing burden of disease, our present treatment options are limited.  Bronchodilator therapy is essentially palliative, while anti-inflammatory therapies including glucocorticoids are associated with significant side effects during long-term use.  Thus there is a pressing need to identify new targets that could lead to improved therapeutic options for chronic lung disease patients.

Regional hypoxia (low oxygen) occurs in the majority of patients with significant lung disease, and is implicated as an important stimulus for pulmonary vascular remodelling.  These changes in vessels ultimately lead to an increase in blood pressure (termed pulmonary hypertension) which can significantly worsen outcome for patients.  We previously carried out a study to determine which proteins cause these lung-selective hypoxic responsive changes.  We discovered that a receptor for the potent pro-angiogenic (causes blood vessel growth) protein CXCL12, namely CXCR7, was significantly increased in the lung (but not in other organs) in response to low oxygen.  We next showed that CXCL12 levels were significantly higher in the blood of pulmonary hypertensive patients and CXCR7 was also elevated in the grossly remodelled vessels of these patients.  Taken together, these findings strongly suggest that signalling via CXCR7 may be particularly important in the lung disease.

In the present proposal, we propose to use a combination of cell and animal experiments, along with clinically relevant human samples, to examine how signalling via CXCR7 effects the growth of blood vessels in the lung. The end goal of this proposal is to identify if this pathway represents a new target for therapeutic intervention for chronic lung diseases.