Mechanisms and biomarkers linking ionising radiation to health effects

Project Leads: Samantha Terry (KCL), Stephen Barnard (UKHSA)
Project Team: Irene Mbutu-Austin (PhD student, KCL)

The dose-effect relationships for ionising radiation, particularly at low doses and dose-rates, are not fully characterised. Radiation exposure(s) can induce a number of biological effects in the body, and we aim to further understand these by investigating DNA and chromosomal damage. Blood samples will be collected from nuclear medicine and positron emission tomography (PET) Centre technologists. We will correlate responses of biomarkers with historical personal dose measurements and carry out in vitro experiments to investigate chronic low-dose radiation exposures in lens epithelial cells and further understand low-dose occupational exposure to the lens tissue in response to recent changes in legislation around lens protection and cataract prevention.

This project is part of an ongoing PhD studentship funded in part by UKHSA and a Colt Foundation Fellowship that started alongside the previous HPRU. Work will be carried out to determine whether within this cohort of technologists, radiation-induced chromosomal aberrations are detectable and/or whether, in general, technologists could be more radiosensitive due to long-term occupational exposure. Ongoing discussions with technologists will help determine priorities in this area relevant to workers’ concerns. Further, we will investigate DNA damage induction from occupationally relevant chronic low-dose radiation exposure of lens epithelial cells, to understand the radiosensitive nature of this tissue and the impact of radiation protection for workers.

Project Leads: Christopher Whiteman (UKHSA), Richard Southworth (KCL)
Project team: Samantha Terry (KCL), Sean Gettings (UKHSA), PhD student KCL

Cardiovascular disease (CVD), which can lead to myocardial infarction (heart attack) or stroke, remains the leading cause of mortality worldwide. The most common underlying cause is atherosclerosis; an inflammatory condition affecting arteries that supply vital organs such as the heart and brain. A key step in the development of atherosclerosis is the damage and activation of endothelial cells (ECs), which line the inner surface of blood vessels. ECs regulate the transport of lipids from the bloodstream into the subendothelial space, where atherosclerotic plaques form. Once activated, ECs promote immune cell recruitment by expressing adhesion molecules and secreting inflammatory mediators.

Established risk factors, such as hypertension, are believed to contribute to CVD by damaging ECs. Emerging evidence suggests a similar mechanism may underlie the increased cardiovascular risks associated with exposure to ionising radiation (IR). Notably, IR-induced cellular senescence has been proposed as a key driver of radiation-associated CVD. Senescent cells undergo structural alterations, metabolic changes, and develop a senescence-associated secretory phenotype (SASP), characterised by proinflammatory signalling that can further promote atherogenesis.

Given the limited research into the effects of radionuclides on ECs, this project aims to investigate how radionuclide exposure impacts the function of ECs derived from both cardiac and cerebral vasculature. The project will investigate senescence-related pathways, mitochondrial metabolic changes, and the contribution of radionuclides to CVD risk. Additionally, as ECs play a critical role in maintaining blood-brain barrier (BBB) integrity, the project will also explore the interplay between cellular senescence and radionuclides on the function of the BBB.

Project Lead: Nora Bourbia (UKHSA)
Project Team: Maria Jimenez Sanchez (KCL), Will Timbury (UKHSA funded PhD student)

Radiotherapy to treat head, neck and brain cancer has important long-term side effects, inducing cognitive dysfunctions and neurological impairment, as well as being an environmental factor triggering flares and onset of diseases (i.e.: dementia with Body Lewis, multiple sclerosis) in patients with predisposition for those diseases.

Amongst brain cells, astrocytes are a brain cell type that play a major role in the maintenance of the neuron. Astrocyte dysfunctions are associated to various neurological process impairment and diseases, including those mentioned above.

Therefore, the aim of the project is to investigate whether radiotherapy affect negatively astrocytes leading to cellular pathological phenotype associated to neurodegenerative diseases.

Human primary astrocyte will be subjected to radiotherapy regimes to then assess cellular metabolism, autography, and mitochondrial functions changes in response to radiation exposure. Cellular metabolism, autophagy and mitochondrial functions are key cellular processes that lead to neurological diseases when dysfunctional.

Project Leads: Grainne O’Brien (UKHSA), Milagrosa Lopez Riego (UKHSA)
Project Team: Paul Elliott (Imperial)

Alterations of the circadian clock, a complex biological system which regulates 24-hour rhythms of physiological processes, have been associated with a higher incidence of cancer development and other health effects such as mental health issues and cardiovascular problems. This study aims to better understand the possible mechanisms linking transcriptional control of circadian clock genes and cancer, ionizing radiation-induced acute myeloid leukemia (AML), in particular. We wish to use biological samples from individuals in occupations involving shift work to investigate potential modifications of transcriptome/epitranscriptome and the impact of circadian gene expression disruption on the response to ionizing radiation (IR) exposure. Our study objectives are: 1) To investigate the transcriptome and epitranscriptome, with an emphasis on the transcriptional expression of clock genes, in human blood samples from people in occupations who have been working night shifts, as compared to non-shift workers. For this we are interested in tempus tubes available at the AIRWAVE biobank from which we could isolate RNA; 2) To investigate the potential impact of circadian clock disruption and transcription phenotype on the DNA damage response following ex vivo irradiation of blood samples from occupational workers conducting night shifts as compared to non-shift workers. For the irradiation of fresh blood samples, we would require the recruitment of participants again to the study. In the long term, the results will inform us on the risks of circadian disruption for leukemia development especially in the context of low dose of radiation exposure and allow us to provide accurate scientific and health advice to the government and the public.

In this project, we wish to perform the first large-scale study on night shift workers to investigate the transcriptional changes of clock genes and the potential impact of circadian state on radiation response. Using a thorough transcriptomic analysis, this work could identify individuals experiencing specific gene expression signature alterations and, importantly for radiation protection purposes, characterise potential underlying mechanisms and the longer-term risk of radiation-induced cancer following exposure to IR.

Project Leads: Mingzhu Sun (UKHSA)
Project Team: Christophe Badie (UKHSA), Graeme Hewitt (KCL), Jayne Moquet (UKHSA), Stephen Barnard (UKHSA)

Lynch syndrome (LS) is the major cause of hereditary colorectal and endometrial cancers, and it is also associated with high lifetime risks of developing tumors at various other sites affecting approximately 1 in 400 persons in the UK. LS patients have an inherited predisposition to cancer due to the deficiency in their DNA mismatch repair (MMR) genes, which may pose an increased risk of cancer development if exposed to ionizing radiation (IR). IR can directly or indirectly damage DNA, and therefore, whether radiotherapy can induce secondary cancer in patients especially those with defective DNA repair system is a major concern in cancer treatment. Till date, there are no clinical data or representative cell lines to study the radiation-induced effects in these patients nor published guidance on the medical use of radiological imaging and radiotherapy whilst neoadjuvant radiotherapy is routinely used for patients with advanced rectal cancer regardless of their MMR status. Thus, it is critical to study radiation effects in cells with MMR deficiency to mimic the radiation treatment effects to assist with clinician’s assessment of the benefit-risk balance in responses to diagnostic, therapeutic and occupational exposures of IR.

Project Leads: Lefteris Livieratos (KCL), Liz Ainsbury (UKHSA)
Project Team: Christophe Badie (UKHSA), Samantha Terry (KCL), Daphne Jackson Fellow at UKHSA

Blood-based biomarkers related to DNA and chromosomal damage may offer a means to monitor systemic radiation exposure and a surrogate to radiation absorbed dose when the later is difficult to obtain. With recent advances in radiopharmaceuticals used in tandem with diagnostic and therapeutic medical applications (theranostics) and their established use in molecular radiotherapy for systemic treatment of cancer, there is an increasing call to establish personalised radiation dosimetry metrics. However, these require extensive radionuclide imaging which is not always available. In this project, blood-based biomarkers related to DNA and chromosomal damage will be examined in samples before and after patients are treated with radionuclide therapy, e.g. 131I for benign and malignant thyroid disease, [177Lu]Lu-DOTATATE (for neuroendocrine tumours), or 223Ra, at Guy’s and St Thomas’ Hospitals. These will be correlated to therapy outcomes, types of radionuclide emissions and estimated radiation dose exposure (from dose rate and radionuclide whole-body retention data). The key objective is to establish metrics which correlate to estimates of absorbed radiation dose estimates based on imaging or internal dosimetry models with input of the administered radioactivity.