Eleven Trinity researchers awarded €4M to tackle global health challenges

The newly announced Investigator-Led Projects for Health (ILP) 2022 from the Health Research Board (HRB) will drive advancements in treatments and therapies across a broad range of human health and disease including neurodegenerative disease, respiratory disease, bloodstream infection, arthritis, cancer, and depression.

The Trinity awardees for 2022 are:

• Professor Clair Gardiner, School of Biochemistry & Immunology
• Professor Cristín Ryan, School of Pharmacy & Pharmaceutical Sciences
• Professor Desmond O’Neill, Professor of Medical Gerontology, School of Medicine
• Professor Eleanor Molloy, Professor of Paediatrics & Child Health, School of Medicine
• Professor Rachel McLoughlin, Professor in Immunology, School of Biochemistry and Immunology
• Professor Ursula Fearon, Professor of Molecular Rheumatology, Clinical Medicine, School of Medicine
• Ussher Assistant Professor Sinead Smith, Clinical Medicine, School of Medicine
• Assistant Professor, Dr Bahman Nasseroleslami, Clinical Medicine, School of Medicine
• Research Assistant Professor, Dr Sharee Basdeo, Clinical Medicine, School of Medicine
• Assistant Professor, Dr Eva Jimenez-Mateos, Physiology, School of Medicine
• Dr John R Kelly, Clinical Lecturer, Psychiatry, School of Medicine

 Trinity’s successful applicants were selected in a national application process, underpinned by rigorous review, including expert international peer review and an applicant response stage, conducted by an independent and international panel.

AWARDEES AND PROJECT INFORMATION

Professor Clair Gardiner, School of Biochemistry & Immunology

Project title: Altered histone protein acetylation is associated with dysregulated NK cell metabolism in different cancer types

Natural Killer (NK) cells are immune cells which normally fight cancer; however, they become exhausted and no longer able to function as cancer progresses. There is some data from patients with metastatic breast cancer suggesting that NK cells may regulate their DNA differently in cancer patients. This project aims to (i) understand why this happens by looking at internal mechanisms within the cell and how they are dysregulated and (ii) investigate if the effects studied are common to other cancers, starting with metastatic melanoma. The project will also investigate how a class of anti-cancer drugs called HDACi impact on the immune system and how treatments can be optimised to improved patient outcome.

It is hoped that this research will improve cancer outcomes for patients with metastatic cancers.  Currently, metastatic cancers are incurable and new approaches and treatments are urgently required. Immunotherapy has already had huge clinical success but is only in its infancy in terms of realising its full potential. Maximising this potential will be achieved by immunologists and oncologists working together for this common goal.

Speaking about the award, Clair said: “Immunology is revolutionising cancer therapies for a range of hard-to-treat, paediatric and metastatic cancers. The concept that metastatic cancers could one day be cured routinely is mind-blowing.”

Professor Cristín Ryan, School of Pharmacy & Pharmaceutical Sciences 

Project title: The development of an intervention to improve the use of point-of-care diagnostics in the management of respiratory tract infections in primary care: a mixed methods study.

Inappropriate antimicrobial use is one of the main causative but modifiable risk factors associated with antimicrobial resistance (AmR), which is now considered to be the next global health pandemic. Most (70%) antimicrobial prescribing occurs in primary care, with up to 50% of this prescribing deemed unnecessary or inappropriate. The inappropriate management (i.e., diagnosis and subsequent treatment) of respiratory tract infections (RTIs) is particularly problematic, with large discrepancies reported between what is prescribed and what should be prescribed, considering the viral aetiologies and self-limiting nature of most RTIs.

Point-of-care testing allows healthcare professionals to make an accurate diagnosis, the first step in ensuring optimal patient management, but this is not routine clinical practice.  This research programme aims to develop an intervention involving General Practitioners and Community Pharmacists in primary care, to improve the use of point-of-care diagnostics in the management of RTIs and test its proof-of-concept.

Speaking about the award, Cristín said: “Antimicrobial resistance is a real threat to health globally. Receiving this award highlights the importance of improving the diagnosis and management of respiratory tract infections to reduce unnecessary use of antimicrobials.  I’m looking forward to working with the multiple stakeholders involved in the delivery and receipt of care to develop this intervention.”

Professor Desmond O’Neill, Professor of Medical Gerontology, School of Medicine

Project title: Planning and design for quality of life and resilience in residential long-term care settings for older people in Ireland: Research and Universal Design Guidelines for new-build, adaption and retrofit.

In Ireland, provision of nursing home design for older people is inadequate, putting pressure on health system and undermining the care of many older people. With population growth, the number of people requiring nursing home care will increase, worsening the shortfall. The success of this care is greatly influenced by design and quality of the physical environment, and their impact on resident and staff wellbeing and health. COVID-19 has exposed how many settings are ill-designed for infection-control and the protection of residents; and illustrated importance of space and spatial practices, for example social distancing and isolation/quarantine, all of which have immediate and long-term implications for nursing home planning and design.

The project will produce evidence-based Universal Design guidelines for nursing home design in Ireland that support quality-of-life and infection-control. Additionally, these guidelines will support resident-centred principles and standards in national policy; be applicable to new-build, retrofit and refurbishment projects; and relate to rural, suburban and urban locations.

Speaking about the award, Des said: “This is an exciting opportunity to address the neglect up to now of person-centred design of nursing homes and plan for a better future for all of us as we age. In collaboration with TrinityHaus Research Centre, this project continues the long-standing practice of inter-disciplinarity between the School of Medicine and Engineering in exploring the role of the built environment and its impact on the health and well-being of people across the life span.”

Prof Eleanor Molloy, Professor of Paediatrics & Child Health, Trinity Institute of Neurosciences

Project title: STARFISH: Sustained inflammaTion in preterm infAnts and multioRgan dysFunctIon correlateS witH long term outcomes.

The global impact of preterm delivery is huge, with an increasing incidence that has long-lasting health and other effects. Children born with a very low birth weight have substantially higher rates of intellectual impairment, poorer executive, academic and motor function, more neurodevelopmental disability, and poorer health-related quality of life than do contemporaneous term-born controls. Some of these outcomes may be deteriorate rather than improve over time and there is a call for new strategies from birth through the lifespan to improve outcomes for these children.

This project aims to further quantify these long-term multiorgan effects and institute early management. This will also correlate with immunological biomarkers to predict outcomes and allow early intervention in at -risk groups. Although biomarker discovery and validation is important in developing a more in- depth knowledge of dysregulated immune function is required to develop specific treatments.

Speaking about the award, Eleanor said: “We are very excited to work with families and experts in newborn sepsis and prematurity to develop consensus definitions and multiorgan follow-up guidelines to improve preterm infant outcomes.”

Professor Rachel McLoughlin, Professor in Immunology, School of Biochemistry and Immunology

Project title: IMPRINT: Defining pathogen-specific IMmune PRedictors of bloodstream INfecTion outcomes.

Antimicrobial resistant infection is now one of the biggest threats to global health. A shocking study published earlier this year estimates that in 2019 alone, 1.2 million people died from an antibiotic resistant bacterial infection. A dwindling pool of effective antibiotics, coupled with lack of commercial incentives for pharmaceutical companies to engage in new antibiotic development has created the perfect storm. Bloodstream infection (BSI) is a significant public health concern with the burden of disease poised to increase exponentially due to the ongoing antimicrobial resistance (AMR) epidemic. 

The IMPRINT project will establish if distinct patterns of immune cells are activated in patients during an infection and if these immune patterns can be utilised to help distinguish what specific bacteria is causing the infection and determine how severe the infection will be in that person. This knowledge can then be used to develop new tools to diagnose infection more rapidly and also to develop new vaccines. Doing so would improve infection management and patient care, ultimately helping to stem the tide of antimicrobial resistance. 

Speaking about the award, Rachel said: “With this HRB Award, we now have an opportunity to advance understanding of infections, for which effective treatments are lacking, such as antibiotic resistant bacteria. Despite the fact that we have been living with and studying the bacteria that cause bloodstream infections for decades, we still don’t fully understand the complexities of how our immune systems respond to them.”

Professor Ursula Fearon, Professor of Molecular Rheumatology, Clinical Medicine, School of Medicine

Project title: Stromal cell subtypes define distinct pathogenesis in RA and PsA

Inflammatory Arthritis such as Rheumatoid (RA) and Psoriatic Arthritis (PsA) are autoimmune diseases associated with significant joint destruction, functional disability, increased co-morbidities and mortality. The costs to the individual and society are high, including economic and social costs - drugs, hospitalizations, lost productivity, reduced quality-of-life and social isolation. RA and PsA are characterized by a spectrum of similar clinical features but there are distinct clinical manifestations. These may explain differences in disease onset and therapeutic response, that impact on early interventions, prognosis and disease outcomes.

Despite advances in targeted biotherapeutics, currently a significant proportion of patients have no/sub-optimal  responses or adverse events. There are no cures, therefore patients require lifelong treatment. This project aims to identify molecular signatures that define disease pathotype and response, in addition to  examining potential new therapeutic targets for those that currently do not respond to any available therapies.

Speaking about the award, Ursula said: “This award allows our translational team of medics, scientists and patients, to apply the latest, most cutting-edge scientific methodology to examine biosamples from patients with inflammatory arthritis to potentially dissect the pathological mechanisms that underline the disease and discover new preventative strategies and new cures for the two most common inflammatory arthritides – RA and PsA.”

Ussher Assistant Professor Sinead Smith, Clinical Medicine, School of Medicine

Project title: Comprehensive characterisation of resistance mechanisms for the accurate detection of Helicobacter pylori antimicrobial resistance

Helicobacter pylori (H. pylori) are bacteria that infect the stomach, causing inflammation and increasing the risk of developing peptic ulcers and stomach cancer.  Treatment involves a combination of antibiotics but has become challenging because of resistance that the bacteria may have to these medicines. 

This research will allow us to better understand the mechanisms of H. pylori antibiotic resistance so that we can detect resistant H. pylori more accurately. This will lead to better patient outcomes through improved treatment choices and H. pylori clearance, thereby preventing the development of more serious diseases such as peptic ulcers and stomach cancer.

Speaking about the award, Sinead said: “I’m really looking forward to working with leading scientists and medical doctors to tackle the problem of Helicobacter pylori antibiotic resistance so that we can develop better ways to detect and treat H. pylori infection and improve patient outcomes.”

Dr Bahman Nasseroleslami (Assistant Professor, Clinical Medicine), School of Medicine

Project title: Effective Subsets of Fine-Grained Network-based Neurophysiological Biomarkers for Early Stratification in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a terminal neurodegeneration of the motor neurons leading to progressive loss of movement and death within 3 years. A crucial challenge in finding effective therapeutics is the lack of biomarkers for early diagnosis and stratification of patients for measuring the response to drugs in clinical trials.

Biomarkers based on the electrical activity (EEG) in different brain networks are quantitative, non-invasive and inexpensive and have the potential to replace traditional qualitative measures of stratifying patient sub-groups and monitoring disease progression. They can rapidly translate the early diagnosis and fast phenotyping of Amyotrophic Lateral Sclerosis (ALS) and related conditions, from research domains to clinical settings. Refinement of patient stratification will enable cheaper and more refined therapeutic clinical trials (benefiting the patients, the health systems, and the pharmaceuticals industry), helping to facilitate the identification of disease modifying drugs in ALS. This will have a direct impact on the quality of life of patients and caregivers living with ALS.

Speaking about the award, Bahman said: “One of the unique aspects of this project is that it aims to convert scientific exploration to scientific exploitation. We and others have been making important discoveries in developing potential biomarkers for Amyotrophic lateral sclerosis (ALS) that have the potential to identify the disease phenotypes and measure the efficacy of the drug in brain networks in the course of clinical trials. This project aims to bring together those interesting but rather scattered discoveries together; hence providing answers on what (combination of) of these interesting discoveries we should actually use in the future trials.” 

Dr Sharee Basdeo Research Assistant Professor, Clinical Medicine, School of Medicine

Project title: Defining how innate immune function is impacted long term in people who have had active Tuberculosis.

TB remains one of the leading causes of death from an infectious agent world-wide. The effects of COVID-19 have caused a TB syndemic. Attention in respiratory research has been diverted to COVID-19, so, it is now more important than ever to intensify TB research to help mitigate against the negative impact COVID-19 has had on TB healthcare.

This research will advance the field of TB host defence, to deliver new treatment options for this neglected global health emergency. By understanding how the innate immune response is altered in people who have recovered from TB, this study will be able to identify therapeutic targets to reduce their risk of subsequently developing active TB.

Speaking about the award, Sharee said: “This HRB ILP 2022 Award affords myself and my team a great opportunity to begin to understand the longer-term impact infections have on our immune system, even after we’ve recovered. We hope our findings have implications that may promote general health and well-being in people recovering from a spectrum of infections; from the mild common cold to more serious infections like TB.”

Dr Eva Jimenez-Mateos, Assistant Professor, Physiology, School of Medicine

Project title: Analyzing the therapeutic potential of anti-inflammatory drugs in brain development, neuronal activity and long-term outcomes after birth asphyxia.

Birth asphyxia or neonatal hypoxia is a medical condition resulting from deprivation of oxygen to a newborn infant that lasts long enough to cause harm. It remains a serious condition which causes significant mortality and morbidity. Neonatal hypoxia is a global insult, which can damage all organs, but the brain is especially vulnerable to hypoxia, making it the special concern for clinicians. Indeed, in a proportion of the infants, brain damage will manifest as either mental, such as developmental delay or intellectual disability, or physical, such as cerebral palsy.

Perinatal asphyxia happens in 2 to 10 per 1000 new-borns that are born at term, The World Health Organization (WHO) estimates that 4 million neonatal deaths occur yearly due to birth asphyxia, representing 38% of deaths of children under 5 years of age.

Speaking about the award, Eva said: “Neonatal brain damage is a detrimental condition that affects not only the infants, but their families, parents and siblings. In this project we will increase our knowledge of neonatal brain which will, first, try to give answers to parents and, second, facilitate to find better treatments.”

Dr John R Kelly, Clinical Lecturer, Psychiatry, School of Medicine

Project title: A translational investigation of the anti-inflammatory and anti-depressant effects of Psychedelics in Depression

There is accumulating evidence showing that psychedelics when administered with psychological support can lead to therapeutic effects for a range of disorders with restricted or maladaptive patterns of thought, emotion and behaviour. This translational project aims to advance the understanding of how psychedelics work by exploring the immuno-modulatory and anti-depressant effects of psychedelic compounds. By enhancing our understanding of the immuno-modulatory properties of psychedelics, this project may also provide insights into how to enhance the therapeutic response rates of psychedelic therapy in depression and other disorders.

The development of psychedelic therapy offers the potential for an additional and effective treatment strategy for people with depression and other disorders. Psilocybin with psychological support could be approved as a treatment for depression in the coming years. This project will advance our understanding of the mechanisms of action of psychedelics and will add to the accumulating evidence base showing the therapeutic potential of psychedelic therapy, with the eventual integration of psychedelic therapy into the Irish public health system for the benefit of the individual, their families and wider society.

Speaking about the award, John said: “This award will bring together clinicians, academics, people with lived experience of depression, public interest voices and industry partners to establish a translational psychedelic science research programme in Trinity College Institute of Neuroscience (TCIN) and Tallaght University Hospital that will deliver tangible benefits to patients, the health service and to Irish society.”

This article was first published on 30 August by Trinity College Dublin.