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Theme 3: Project 1 - Novel human cell model of atherogenesis

We have demonstrated that ionising radiation (A) causes the apical surface of endothelial cells to become highly adhesive and (B) disrupts the production of junction proteins that hold adjacent endothelial cells together. These features increase the risk of atherosclerotic plaque formation because they facilitate the entrapment and passage of monocytes and LDL across the endothelium into the arterial wall. These findings explain at least in part, the curious epidemiological association between exposure of the heart to ionising radiation and subsequent increased risk of cardiovascular disease. The underlying molecular mechanisms have been elucidated and published: Lowe and Raj (2014) Ageing Cell and Kabacik and Raj (2017) Oncotarget.

The next phase of this research programme is predicated on two identified features: (1) pro-atherosclerotic properties are only exhibited by irradiated cells that have become senescent and (2) these properties are not acquired through mutations generated by ionising radiation. The former would suggest that radiation may be particularly detrimental to young tissues, which naturally have very few senescent cells, but it is questionable whether exposure of older tissues, which naturally already have many senescent cells bear equal risk.

This is an important health protection question especially in the context of rising use of scans in medical procedures in general and the increasing need for scans among the elderly. Hence, from April 1 2018 to March 31 2020, we will address the question of age effect on radiation risk. Secondly, as the radiation effects described above are not mediated by mutations, we will characterise non-mutational effects of ionising radiation that can potentially affect cell physiology and function. This will inform on whether there may be other non-cancer diseases that could be induced by ionising radiation that are presently not known or appreciated. 

Lead researchers

Dr Ken Raj

Investigator

Public Health England