Trinity health researchers win 11 HRB awards valued at €4.75m

Posted on: 17 September 2024

The funding to Trinity researchers is part of a €12.4m investment from the HRB to address health challenges.

The awards for Trinity will support individual projects investigating health areas that include oncology, Alzheimer’s disease, cerebral palsy, cancer survivorship, arthritis, healthy ageing, and rheumatoid arthritis.

Trinity won 11 awards out of a total of 29 from the HRB.

Responding to today’s announcement, Professor Brian O’Connell, Dean of the Faculty of Health Sciences, said:

“ We are delighted to see 11 Investigator-Led Projects by Trinity College investigators funded by the HRB. These projects are focused on improvements in human health and included a review by the public in addition to scientific peer review. The research will build on strengths across health sciences in Trinity, from understanding disease, to better treatments and enhanced quality of life for patients. There is no doubt that the work of these talented researchers will generate lasting insights for patients suffering a range of devastating diseases.”

The 29 successful investigator-led projects were selected by an international panel of experts following a rigorous application process. A public review was undertaken alongside the scientific peer review to assess whether the research is in the best interests of the patient or the general health of the population. Successful projects were selected based on their scientific quality and innovation, potential impact, and feasibility.  The ILP is the HRB’s largest award scheme.  

Dr Mairead O’Driscoll, Chief Executive at the Health Research Board, said:

“The ILP scheme illustrates the HRB’s commitment to support high-quality investigator-led research. We want to create new internationally relevant knowledge that will help to address major health challenges in society. And we want to make a positive impact on tomorrow’s health care.”

 

A full list of all the successful Trinity awards is available below:

11 awards, total value: €4,754,456

Lead Applicant: Professor Joanne Lysaght

Project: Combination targeting of immunosuppressive sialylation and immune checkpoint pathways to maximise T cell responses in cancer

Patient-Oriented Research

Award Amount: €428,054

Lay summary

Oesophageal adenocarcinoma (OAC) is a dismal prognosis cancer, whose incidence continues to increase year on year. Recent approvals by the FDA and EMA/HPRA allow for the use of novel immune-based therapies, including anti-PD-1 targeting agents in advanced OAC patients. While immune checkpoint inhibitors (ICIs) have revolutionised the field of cancer immunotherapy, engaged public interest and offered the possibility of cure for some patients, overall the response rates to ICIs remains poor, estimated to be from 13-29% across all cancers. Current clinical trials are focusing on combining different ICIs or combining with chemotherapy/radiotherapy and assessing treatment scheduling, but few are currently targeting immune evasion strategies in combination with ICIs. This is a critical feature which is likely responsible for the poor response rates to ICIs across multiple cancer types and therefore future approaches should aim to counteract immunosuppressive pathways along with immune stimulatory therapies, such as ICIs.

This project aims to target an emerging evasion strategy used by solid tumours, which is the Siglec-sialic acid pathway. This pathway is dysregulated in tumours, with an overexpression reported in many solid tumours and is involved in the majority of cancer hallmarks, most notably immune evasion. Specific Siglec receptors are involved in T cell suppression including Siglec-7, -9 and -10, which will be the focus of this study. This project will examine sialylation and the expression of Siglec ligands on both OAC tumour cells and mesenchymal stromal cells under different biologically and clinically relevant conditions, reflective of the tumour microenvironment and cancer treatments. This study will also assess how T cells are suppressed through the Siglec-sialic acid pathways and how targeting this pathway could enhance T cell function. Lastly, we will investigate how dual targeting of ICIs and sialylation could enhance T cell function and ultimately improve outcomes for patients who receive ICIs.

 

Lead Applicant: Professor Aisling Dunne          

Project: Evaluation of novel modulators of oxidative stress as add-on pharmacotherapies for rheumatic disease

Patient-Oriented Research

Award Amount: €453,578

Lay summary

It is estimated that approximately 18 million people worldwide suffer from rheumatoid arthritis (RA). Current immunosuppressive treatments have clinical efficacy; however many patients suffer severe side effects and approximately 50% of patients are refractory to therapy. This highlights the need for more diverse anti-inflammatory treatment options, which are well tolerated and have long-term efficacy in patients. One notable feature strongly associated with RA is tissue destruction and inflammation caused by oxidative stress. This is unsurprising given the persistent hypoxic conditions in the RA synovium. Numerous studies have verified that activation of the Nrf2 system (a master regulator of oxidative stress) may be therapeutically beneficial for ameliorating RA owing to its anti-inflammatory and anti-oxidative activity. This is mediated largely by protective enzymes including heme oxygenase-1 (HO-1). We previously reported that keto acids produced by the parasite, Trypansoma brucei (as well as commensal bacteria in the gut), activate Nrf2 and can directly suppress inflammatory responses and dysregulated metabolism in human immune cells, via HO-1 activation. Most recently, we have generated novel data demonstrating that these compounds can promote stem cell differentiation and induce the expression of genes associated with bone/cartilage formation. The purpose of this study is to determine if these compounds have potential for use in the treatment of RA, given the strong connection between oxidative stress and tissue damage in this disease. Of note, indole-based products have recently been highlighted as promising therapeutics for inflammatory bowel disease and parasite derived products have long been explored as anti-inflammatories to treat a range of autoimmune and inflammatory diseases. Validation of these molecules in RA patient samples and in stem cells will support future studies that could potentially lead to the development of new RA therapies.

 

Lead Applicant: Dr Lucy Norris    

Project: PINPOINT: PredIction aNd Prevention Of Venous Thrombosis durINg chemoTherapy- combining dynamic biomarker risk assessment, patient perspectives, and health technology assessment

Patient-Oriented Research

Award Amount: €428,664

Lay summary

Venous thromboembolism (VTE) is the leading cause of non-cancer death in cancer patients. Patients are particularly at-risk during chemotherapy where rates of up to 20% have been reported.  Guidelines recommend primary prophylaxis with direct oral anticoagulants (DOACs) in intermediate/high risk patients undergoing chemotherapy following risk assessment with a validated risk score (Khorana score). However, the Khorana score performs poorly in lung, ovarian and gastric cancers and relies on a single assessment at the start of therapy.

The development of VTE is a dynamic process which cannot be accurately represented by a single risk assessment. Our data suggests that markers of procoagulant activity are implicated in chemotherapy associated VTE and could be measured serially as predictive biomarkers. This may provide a more effective method of identifying patients at risk of VTE and facilitate targeted prophylaxis. 

Prophylaxis with DOACs carries a risk of bleeding hence decisions regarding prophylaxis should be shared between doctor and patient.  However, studies have shown that cancer patients receive limited information about VTE risk and tools to aid decision making in this area are lacking. Cost is also a consideration for both the health service and the patient.

In this study we will:

• measure procoagulant biomarker levels serially during chemotherapy as dynamic predictors of VTE.
• investigate the prothrombotic mechanisms involved in chemotherapy associated VTE.
• identify patient needs and priorities for shared decision making with regard to prophylaxis during chemotherapy
• perform a cost benefit analysis of biomarker screening and targeted VTE prophylaxis during chemotherapy

This study aims to develop dynamic predictive biomarkers for VTE during chemotherapy and to understand patient priorities with regard to VTE prevention during chemotherapy. Identification of high-risk patients and increased understanding or patient priorities and costs will lead to effective shared decision between doctor and patient ultimately reducing the burden of VTE in cancer.

Lead Applicant: Professor Ursula Fearon          

Project: Distinct Immune-Stromal cell Interactions are involved in the underlying mechanisms that distinguish RA and PsA pathotypes.

Patient-Oriented Research

Award Amount: €453,249

Lay summary

Two of the most common forms of inflammatory arthritis are rheumatoid arthritis (RA) and psoriatic Arthritis (PsA). Common pathogenic features exist between RA and PsA, however significant differences are observed at the clinical, immunological, cellular, and molecular levels. While some therapies are effective in both patient groups, different responses have been demonstrated to new targeted therapies. At a molecular single-cell level little is known about the distinct underlying mechanisms involved in driving this differential pathogenesis in the target tissue of disease ‘the-synovium’. Two of the most prominent cell-types in the RA and PsA synovium are macrophages and fibroblasts (FLS), which play a key role in joint inflammation through immune-cell regulation, potent secretion of pro-inflammatory mediators and synovial invasion of adjacent cartilage and bone.  Recently, using advanced flow-cytometry and scRNAseq, we identified significant enrichment of a dominant macrophage-subtype CD206+CD163+ co-expressing CD40+ in RA inflamed synovial-tissue compared to healthy-control, and have shown in co-culture that RA sorted macrophages induce a proinflammatory phenotype in FLS. Preliminary data also demonstrated significantly higher frequency of Thy1+FAPα+FLS in RA compared to PsA, thus demonstrating functional diversity of macrophage/FLS cellular phenotypes in the joint.  In parallel, we have identified that circulating monocytes in RA and PsA differ, an effect that is memorised in monocyte-derived macrophages. Finally, preliminary data from scRNAseq analysis has shown distinct receptor-ligand interactions between macrophages-FLS that potentially drives the Thy1+FAPα+FLS subtype in RA compared to PsA. Therefore, in this project, using advanced flow-cytometry, scRNAseq, metabolic-analysis along with extensive mechanistic studies using physiologically relevant patient models of RA/PsA disease we will (i) examine circulatory monocyte function and activation, (ii) determine distinct synovial tissue macrophage-FLS crosstalk in RA and PsA, (iii) correlate with disease-activity, progression and response and (iv) identify new targets for novel therapeutic strategies in ‘pre-clinical proof-of-concept studies’ using ex-vivo models of RA/PsA disease.

 

Lead Applicant: Dr Sharee Basdeo          

Project: Inducing respiratory trained immunity for TB host defence in the human lung.

Patient-Oriented Research

Award Amount: €428,996

Lay summary

Tuberculosis (TB) is a leading cause of death from an infectious agent. Globally, there has been a marked increase in TB incidence and drug-resistant TB in the past two years. There is an urgent unmet clinical need for host-directed therapeutics and prophylactics capable of inducing effective respiratory immunity against the bacteria that causes TB; Mycobacterium tuberculosis(Mtb).

Since the tissue resident alveolar macrophage (AM) is the first cell to encounter Mtb in the human lung, and the cell that becomes chronically infected leading to TB disease, supporting the immune function of this population, and the lung resident cells in proximity, is a rational therapeutic strategy to promote immune defence against Mtb infection.  Myeloid cells from the bone marrow have a capacity to be ‘trained’ towards enhanced host defence. Our recent work has shown that a COVID-19 adenovirus-vectored vaccine 'trained' monocytes towards enhanced non-specific immune responses to Mtb. Our collaborator showed that aerosolised delivery of an adenovirus vectored vaccine against Mtb elicited immunity in the lung whereas intramuscular vaccination did not. Evidence from murine models of respiratory mucosal adenovirus vaccination indicates that murine AM can be 'trained' resulting in enhanced immunity to bacterial infection mediated by improved kinetics of myeloid cell recruitment. However, a significant knowledge gap human remains as to whether tissue resident human AM can be trained to promote immunity to Mtb, and the mechanisms inducing and propagating trained immunity in the human lung. 

This project will be the first to define the induction of trained immunity in human AM through evidence of functional and phenotypic changes in the human AM, underpinned by metabolic and epigenetic reprogramming. These crucial data will define the human AM as a critical target for respiratory mucosal prophylactic or therapeutic vaccination, enabling the translation of trained immunity towards the global effort to ‘End TB’.

Lead Applicant: Dr Mary Canavan          

Project: Restoration of Immunological Tolerance in Rheumatoid Arthritis via Metabolic Reprogramming of Dendritic Cells

Patient-Oriented Research

Award Amount: €428,997

Lay summary

Rheumatoid Arthritis (RA) represents a major global public health challenge with approximately 1% of the world’s population suffering from this autoimmune musculoskeletal disease. The disease follows a variable course in which periods of remission followed by disease flare are common. As such, in the absence of a cure, patients require ongoing and very often lifelong treatment.

While environmental, genetic, and epigenetic factors have all been linked to the development of RA, a key, initiating factor in disease development is the loss of immunological tolerance to self-antigens. Dendritic cells are widely accepted as having a nonredundant role in maintaining and controlling this tolerance to self-antigen whereby the breakdown of this function is a driving force in the onset of many autoimmune diseases. Therefore, therapeutically targeting DCs in a disease setting such as RA, may provide a unique opportunity to act as a molecular switch, moving DC away from autoreactivity towards tolerance. While previous groups have explored strategies to switch immunogenic DCs to tolerogenic cells or increasing the frequency or function of regulatory cells, strategies aimed at repairing or restoring dysfunctional tolerogenic DCs in vivo have yet to be explored.

In this study we will examine the role of in vivo tolerogenic DC (TolDC) for the first time. Specifically, we will examine the frequency, function, and metabolism of TolDC within the circulation in addition to synovial tissue and synovial fluid. We will determine if dysfunctional TolDC drive the initiation and progression of RA by examining patients from across the spectrum of disease from individuals at risk (IAR) of developing RA (or pre-RA) to early and established disease. Finally using unbiased computational sequencing approaches we will identify targetable pathways in RA that may restore immune tolerance, thus limiting synovial inflammation and progressing treatments to that which have more curative potential.

Lead Applicant: Professor Eleanor Molloy        

Project: The ALPACAS project: ALtering Persistent inflammation And multiorgan outcomes in children at high risk of Cerebral pAlSy

Patient-Oriented Research

Award Amount: €428,450

Lay summary

Background: Cerebral palsy (CP) is a common cause of disability and mortality and represents a massive global burden of disease with 17 million people estimated to be affected worldwide. In addition to neurological complications, multi-organ dysfunction (MOD) is increasingly recognised and is associated with negative lifelong impacts. There is no known cure for CP and the exact cause is often not determined so we aim to integrate neuroimaging, genomics, perinatal data, and biomarkers to improve sub classification of the aetiology of CP.

Lifespan care and multiorgan dysfunction: There is a lack of integration of care for people with CP across the life-course and no standardised management of MODs. We will quantify the degree of multi-organ dysfunction across the lifespan to allow earlier prediction of multiorgan outcomes and the development of precise multidisciplinary therapy for CP using multiorgan biomarkers.

Immune responses and persistent inflammation in CP: Persistent inflammation is well-described in animal models after neonatal brain injury correlating with neurodevelopmental issues and more recently in humans by our group. Irrespective of the cause of CP immune function dysregulation correlates with functional deficits in animal models and human infants and children. We will evaluate whether persistent dysregulated immune function in infants, children, and adults with CP links with clinical outcomes. Detailed immunophenotyping across the lifespan may have benefit as a biomarker of function, outcomes and to guide response to therapy.

Personalised therapies: Individual immunophenotyping and individual responses to in vitro medications such as melatonin will assist in the development of personalised therapies for CP. This unique national and international project involves families and people with CP throughout and has the potential to transform the diagnostic processes, the multi-organ management, and the creation of integrated evidence to increase function for all people with CP across the lifespan.

Lead Applicant: Professor Lorina Naci   

Project: Longitudinal deep phenotyping in the international multi-site programme ‘PREVENT Dementia

Patient-Oriented Research

Award Amount: €452,648

Lay summary

There is now consensus that neurodegenerative disease, including Alzheimer’s disease (AD), starts in mid-life and manifests in later life as dementia and related disorders, but the understanding of early disease mechanisms is lacking. The PREVENT dementia programme is the world’s largest study investigating the origins and early diagnosis of dementia in a mid-life “at risk” cohort. It has recruited and deeply phenotyped 700 participants aged 40-59, across five centres in the UK, and at Trinity College Dublin, in Ireland. Core assessments include cognitive testing, neuropsychiatric evaluation, genetics, lifestyle risk factor analysis, and multi-modal MRI imaging, with samples of blood, urine, saliva, and CSF collected. The programme has undertaken recruitment, with wave 2 (3 year) follow-up in all sites with excellent retention, and wave 3 (7 year) follow-up ongoing in the UK sites. This application seeks funding to carry out wave 3 at Trinity College Dublin.

Our findings have already had great impact, identifying early cognitive, vascular, metabolic, and structural changes that develop 20 years before disease onset, and providing key evidence defining the optimal age to target early therapeutics. This unique dataset at 3 waves, as participants approach symptomatic stages, will address key mechanistic and diagnostic questions, including the relationship between progressive vascular, metabolic, and brain functional and structural changes as the disease develops.

This pathophysiological mechanistic understanding will be critical for identifying (a) novel, early and sensitive biomarkers, (b) tractable mechanisms for targeting therapeutics and designing clinical trials, and (c) how and when to optimally apply new diagnostic tools and biomarkers for early dementia detection. The project will significantly enhance Ireland’s competitiveness in knowledge generation, human capacity, health and wellbeing, professional services, and international engagement.

 

Lead Applicant: Dr Colm Cunningham   

Project: Understanding new brain injury in hip fracture patients

Patient-Oriented Research

Award Amount: €428,458

Lay summary

Hip fracture has negative consequences for the brain. Many patients develop delirium, a psychiatric condition during which they may lose their ability to process or sustain attention to what is happening in their environment and also may experience distressing and fearful periods of days to weeks. Although delirium is acute onset and usually transient it has become clear that these episodes are associated with new dementia diagnosis, acceleration of existing dementia and shortened time to permanent institutionalisation and/or death. How hip fracture causes these negative effects is not clear. Using blood and cerebrospinal fluid (CSF) from 470 hip fracture patients and 180 Alzheimer’s disease (AD) patients, we have recently demonstrated that this acute inflammatory trauma triggers new brain injury as measured by the neuroaxonal injury marker neurofilament light chain (NfL). In this proposal, in order to identify pathways to this acute brain injury, we will use blood and CSF from these same patients to identify and quantify molecules and pathways involved in energy metabolism and inflammation that are activated in these patients. We will integrate our findings from humans with a unique set of experiments in a custom-designed experimental mouse model. We will use the APP/PS1 mouse model for AD (transgenic mice carrying a human double mutation that leads to early onset AD in humans) and challenge these mice peripherally with IL-1ß in order to induce acute systemic inflammation. We will then examine acute cognitive impairment and new brain injury and will use innovative chemical sensors to examine brain bioenergetic changes in real-time, measuring glucose, lactate, and oxygen in the brain. We will then test potential therapeutic interventions that may protect the brain against injury. We hope to elucidate mechanisms driving this injury, in order to move towards treatments that may mitigate delirium and slow dementia progression.

 

Lead Applicant: Dr Emer Guinan 

Project: Personalised Exercise Rehabilitation in Cancer Survivorship (PERCS) 2.0 – Developing an Evidence-Informed National Implementation Strategy

Health Services Research

Award Amount: €411,634

Lay summary

Background: Compelling evidence from randomised trials shows that exercise positively impacts physical, psychosocial, and disease-related outcomes for cancer survivors [1-6]. Oncology guidance is explicit that we must implement exercise into cancer care. To achieve this, the research team developed PERCS, a triage and referral system which assess patients’ level of exercise need and refers patients to suitable exercise services.  PERCS 1.0 (January 2022-October 2023) tested the feasibility of the system, demonstrating high patient acceptability and improvements in physical activity levels.

Aim: The aim of PERCS 2.0 is to develop a cost-effective strategy for national implementation of the PERCS system as a means of advancing integration of exercise into cancer care.

Methods: Work stream 1 aims to estimate the cost effectiveness of PERCS using a model-based simulation. Drawing on best available evidence (i.e., systematic reviews, PERCS 1.0 and evidence emerging in PERCS 2.0), the effectiveness of PERCS in improving QALYs will be estimated. We will gather evidence related to the required resourcing to implement PERCS, the cost (and expected budget impact) of PERCS, including downstream out-of-pocket costs (or subsidies) of exercise programs in the community. Finally, by considering wider healthcare use for cancer patients, reduction in total cost and the incremental cost effectiveness of PERCS will be estimated.

Work stream 2 will develop an implementation strategy for PERCS. Using the Consolidated Framework for Implementation Research (CFIR) we will work with stakeholders from healthcare, community, policy, and patients to identify the barriers and facilitators to embedding PERCS. We will identify potentially relevant individual strategies from the ERIC (Expert Recommendations for Implementing Change) taxonomy of implementation strategies to address barriers using the CFIR-ERIC matching tool. Finally, we will work with stakeholders to select the most important strategies, determine what they will look like in our context, and co-design a multi-faceted implementation strategy.

 

Lead applicant: Professor Rose Anne Kenny    

Project: ProjectHealth: Projecting 20-year Multimorbidity trends and their effect on Health Care Usage, Costs and Quality of Life in older Irish adults

Population Health Research

Award Amount: €411,728

Lay summary

Global population ageing has reached unprecedented levels. But for many, living longer means living with increased levels of disease and disability. In Ireland 91% of individuals aged 50+ have ≥1 chronic disease and 75% have ≥2, known as multimorbidity. This demographic ‘greying’ of the population with concomitant increases in older people living with multimorbidity presents a challenge to the sustainability of our healthcare, welfare, and social care systems.

Health and social care reform is currently progressing under the cross-government Sláintecare plan, which will deliver equitable needs-based access to services. Sláintecare implementation requires robust population-level evidence of current and projected need to ensure strategic service planning and delivery to manage soaring multimorbidity. This includes robust forecasts of health care service usage and costs.

The ProjectHealth (Projecting 20-year Multimorbidity trends and their effect on Health Care Usage, Costs and Quality of Life in older Irish adults) research programme will address this knowledge gap with data-based evidence. ProjectHealth will tackle the health and social care challenge of multimorbidity by characterising multimorbidity trajectories, identifying which disease combinations impact on early mortality and quality-of-life and providing projections for service planning and delivery. Co-designed by the Irish Longitudinal Study on Ageing (TILDA), and the Health Service Executive (HSE), ProjectHealth will use data from TILDA, a study on adults aged 50+ in Ireland, to:

• Conduct cutting-edge research into multimorbidity trajectories
• Provide 20-year projections of multimorbidity prevalence, health care usage and costs
• Investigate how multimorbidity impacts on quality and quantity of life

ProjectHealth will address national and international knowledge gaps in multimorbidity and will directly impact on service and resource planning for the HSE. The outputs of this research will lead the way to determine future studies to develop targeted intervention and prevention strategies for multimorbidity to improve health, wellbeing, and quality of life.

 

READ: You can read the full HRB announcement at this link: https://www.hrb.ie/news-stories/funding-updates/hrb-invests-e12-4-million-in-research-to-address-health-challenges/

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