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Cellular senescence, oxidative stress and inflammation play a critical role in normal human ageing and in the progression of several age-related pathologies. Indeed, cellular ageing has been associated with an increased production of reactive oxygen species and an impairment of cellular defenses against oxidant-mediated insults. Moreover, ageing has also been viewed as a progressive collapse of defense and repair functions that leads to functional decline. These changes are associated with a progressive accumulation of oxidized proteins, degeneration of biological functions and increased susceptibility to diseases such as cardiovascular diseases. Thus for example, there is evidence showing a decline with age of thioredoxin-1 (Trx-1), a critical protein for the protection against oxidative stress and inflammation. This decline can be attributed, in part, to the cleavage of Trx-1 by two a-secretases resulting in the truncated protein, Trx-80. Both Trx-1 and Trx-80 can be secreted and exert contrasting roles. Indeed, Trx-1 exerts antioxidant and anti-inflammatory effects, while Trx-80 has powerful pro-inflammatory effects leading to enhanced atherosclerosis in mice. Our goals are to elucidate the role of oxidative and related protein modification as well as protein maintenance (i.e. oxidized protein degradation by the proteasome and repair by the methionine sulfoxide reductases) during cellular ageing ex vivo and in vitro and in situations of oxidative stress that accelerate ageing. We will use relevant human cellular models (cell lines and primary cells). We will also investigate the mechanism through which Trx-1 protects against oxidative stress. The result will help to translate these findings into new therapies based on Trx-1 peptides. Furthermore, we will investigate the role of the Trx-80 in vascular cellular senescence and inflammation in cell culture and in transgenic mice overexpressing Trx-80. Finally, the relationship between oxidative stress, protein homeostasis and circadian rhythmicity, which is also affected by age, will be investigated in relevant human cellular models (e. g. cell lines, macrophages). In addition, we will examine the impact of circadian rhythmicity on Trx-1/Trx-80 expression and its consequences on the occurrence of cardiovascular diseases.
This work provides the biochemical bases for understanding oxidant/antioxidant and inflammatory alterations to protein function, which are fundamental to understanding the development of pathologies during our lifetime, a key objective of the Unit.
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