Four important clinical research projects led by academic clinicians in the School of Medicine, Trinity College Dublin now have the support of the Royal City of Dublin Hospital Trust. The awards will enable the generation of new knowledge with the long term impact of solving major health problems faced by our society, while also providing a continuum of support to retain our top research talent.

The four awardees will investigate improved care and treatment pathways for significant health challenges including: Tuberculosis (Prof. Gleeson), Ovarian Cancer (Dr O’Toole), Moderate Aortic Stenosis (Prof. Maree) and Immunothrombosis (Prof. Keane).

More detail on each new award are outlined below.

Royal City of Dublin Hospital Trust Project details:

1. Title of Research Project 

Restoring the Smoker’s Immune Response to Tuberculosis with Host-Directed Therapy

Name, Title  of Lead PI 
Laura E. Gleeson, Associate Prof of Respiratory Medicine

Tuberculosis is responsible for 1.5 million deaths annually. Due to the increasing incidence of drug resistance, huge energy is being directed towards understanding host defence strategies, in an effort to develop “host directed therapies” to circumvent drug resistance. Smoking is a major risk factor for TB, with more than 15% of active cases each year attributed to cigarette smoking directly, and smokers’ macrophages have dysfunctional metabolic and functional immune response to TB.
The overarching aim of the research is to show that monocyte-derived “interstitial macrophages” present in Smokers’ lungs have defunct metabolic and functional responses to Mtb, and that these responses can be “rescued” by Vorinostat.

This proposal will delineate a crucial defect in the circulating monocyte-derived macrophage subpopulation within the smoker’s lung, and to assess the viability of repairing this defect to restore function using an FDA-approved oral agent. If successful, this has potential to identify an anti-TB host-directed therapy for the cigarette smoker (of whom there are 996 million worldwide). It is likely that results will be applicable to a range of other respiratory pathogens to which smokers are particularly susceptible. The results of this study will also yield important knowledge about the smoker’s lung which may be applicable to non-infectious smoking-related lung diseases such as lung cancer and COPD.

Speaking about the award, Prof Gleeson said: 

 This award will help us to ask why smokers are so susceptible to TB, and what we can do to fix it

2. Title of Research Project 

Integrating Radiomics into Ovarian Cancer Management

Name, Title  of Lead PI 
Dr Sharon O’Toole, Senior Research Fellow

This study aims to incorporate data from radiological imaging and pathological features to improve on the current prognostic and predictive markers. According to the radiomics principles, images are more than pictures, they are data, and as such they contain a huge amount of information that cannot be analysed visually but need a deep level of analysis. Radiomic features can be used to obtain information about heterogeneity and have the potential to uncover disease characteristics. This project aims to build a model to identify predictive and prognostic features of High grade serous ovarian cancer and to correlate with clinical outcomes. The aim is to go beyond size or human-eye based semantic descriptors, to enable the non-invasive extraction of quantitative radiological data to correlate them with clinical outcomes or pathological characteristics.

Ireland has the poorest outcomes from ovarian cancer in the European Union. Most women are diagnosed when the cancer has spread or metastasised. Although many respond well initially, unfortunately the tumour grows back and fewer than 20% of patients will become long-term survivors.

Identifying patients at risk of poor response to standard treatment remains a critical unmet need. Improved risk stratification models would aid gynecologic oncologists in selecting primary treatment, planning surveillance frequency, making decisions about maintenance therapy and counselling patients about clinical trials of investigative agents.

 Speaking about the research, Dr O’Toole said: 

The addition of radiomic features has the potential to lead to more accurate algorithms for patient stratification.

3. Title of Research Project 

Heart Rate Recovery Velocity as a Marker of Autonomic Dysfunction in Moderate Aortic Stenosis

Name, Title  of Lead PI 
Prof Andrew Maree, Consultant Cardiologist (St James’s Hospital). Affiliated institutions: Cardiology Dept and MISA Institute, St James’s Hospital.

Collaborators Researcher- Dr Niall Connolly; TILDA research group

The objectives of this research are:

  1. To confirm that patients with moderate aortic stenosis have evidence of autonomic  dysfunction when compared to age and sex matched controls.
  2. To confirm that patients with moderate aortic stenosis have a lesser degree of autonomic dysfunction than patients with severe aortic stenosis.
  3. To confirm that the degree of autonomic dysfunction correlates with rate of progression of aortic stenosis and will thereby facilitate risk stratification.

We aim to determine how closely autonomic function correlates with frailty, aortic valve echo parameters and whether it declines over time as the vascular disease progresses. We also intend to determine if blood biochemistry and specifically BNP and troponin levels correlate with autonomic function in this cohort.

We believe that a better understanding of how autonomic function relates to valvular heart disease will allow us to identify patient subjects at highest risk for progression to severe aortic stenosis and who may be suited to early valve replacement. Ultimately, we intend to formulate of a risk score incorporating anatomical factors, autonomic dysfunction and symptoms that may facilitate earlier valve intervention and mitigate risk. We will then test that risk score prospectively in multicentre cohort study.

Speaking about the award, Professor Maree said: 

We have a rapidly expanding technology in transcatheter aortic valve replacement (TAVR) that has clear mortality benefit. We are trying to better understand how that mortality benefit is achieved and to identify patients earlier that may benefit through the study of TAVR impact on cardiovascular autonomic function. With the support of RCDHT this is the 4th MD project we have been able to perform in this field.” 

4. Title of Research Project 

Immunothrombosis and TB and COVID

Name, Title  of Lead PI 
Prof Joseph Keane, Head of Department of Clinical Medicine

The burgeoning data surrounding the COVID-19 pandemic, has firmly pointed a finger at immunothrombosis as a potent aspect of the disease, that has otherwise killed millions. In that regard COVID-19 disease is characterized by high D dimers, and postmortem evidence of in-situ pulmonary thrombosis, which interferes with pulmonary function in this lethal pneumonia – similar to what occurs in tuberculosis (TB). Of interest, signals of infectious disease driven inflammation share common pathways with infection-related thrombosis.

Clots are an important aspect of tuberculosis (TB) disease: It's notable that D-dimers are more elevated in tuberculosis compared to controls of community acquired pneumonia. Furthermore, clotting in tuberculosis postmortem samples are documented by AR Rich al 1946 (The Pathogenesis of Tuberculosis). Pulmonary TB induces a systemic hyper-coagulable state. Kager at al showed that coagulation is turned on (elevated thrombin-antithrombin complexes, D-dimer, and fibrinogen) and anti-coagulation pathways are decreased (reduced plasma anti thrombin, protein C activity, free protein S, and protein C inhibitor) in tuberculosis (TB) patients.

Why is this research important? The consequences from TB-related clotting are evident, as thrombosis in the lung will drive pathological pathways, in diseased tissue. Furthermore, tuberculosis drugs should be delivered to the infected area via the vasculature; so in situ thrombosis might well interfere with drug penetration via clotted cells. Models of clotting in COVID, often do not use primary human lung cells, and this research gap will be addressed here. For these reasons, it is proposed to model infection with tuberculosis or COVID, using established cellular techniques in our laboratory. 

 Speaking about the award, Professor Keane said: 

The group at Trinity/St. James's, who study tuberculosis in our research lab, are excited to receive this support from the Royal City of Dublin Hospital Trust, to perform biomolecular research - that can lead to new therapies. We have learned so many important lessons from COVID-19, such as the role of clots in pneumonia disease. These lessons can now also be applied to other pneumonia types- like tuberculosis. This funding will have a massive contribution in our efforts to train researchers and educated healthcare workers in the important disease of tuberculosis. This is especially important in Ireland, where the rates of multiple-drug-resistant tuberculosis, by dint of the influx of refugees, has gone up six fold in the last year. This funding will also support our efforts to extend tuberculosis care to marginalized members of society who are vulnerable, like persons in prison.