Can the cytoprotective heat shock proteins be specifically targeted to eliminate senescent T-cells?
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MSCA-2020-RNjemini01
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Beschrijving van het project
Immunosenescence (IS) describes the set of changes that occur in the immune system, resulting in a weakened immune function as we age. IS is characterized by increased susceptibility to infections, cancers, and age-related inflammatory diseases, all of which are associated with a higher mortality rate in the elderly. Within the cells of the immune system, an age-associated restriction of naive T-cells in conjunction with an accumulation of senescent T-cells (provoking inflammation) are key contributors to IS. While major insights into IS have been gained, the mechanisms required to counteract IS have not been unraveled. Our previous investigations have confirmed the increase with age, not only of senescent T-cells, but also of several heat shock proteins (HSPs). Moreover, we observed that training induces a decrease in the number of senescent T-cells, as well as HSP70 levels in T-cells. HSPs protect cells from various insults and favor survival. Within the current proposal we will try to understand the role of HSPs on T-cell survival during the generation and maintenance of senescent T-cells. Our primary hypothesis is that in ageing, HSPs protect cells from undergoing apoptosis - and up-regulate survival proteins - thereby promoting their potential for survival. By using ex-vivo highly purified cell populations and an in vitro model, the objectives will be: Objective 1- To specify the molecular mechanisms responsible for HSP expression in T-lymphocytes; Objective 2- To explore the protective role of HSPs in senescent T-cells. Understanding the pathway by which normal T-cells become senescent T-cells endowed with long-term persistence is key to define the mechanisms involved in immune protection and to design strategies to enhance or suppress specific immune responses. In this context, the research project in my proposal will provide novel insights into molecular mechanisms dictating the fate and nature of senescent T-cells.
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Frailty in Ageing Research Department
The Frailty in Ageing (FRIA) research department at the Vrije Universiteit Brussel is a clinical and research team that typically represents multidisciplinary competence, needed for both fundamental and clinical research on frailty in the elderly.
Frailty is a complex geriatric syndrome characterised by a state of increased vulnerability at higher age. There is growing evidence for the involvement of inflammatory processes in the development of frailty. Frail elderly subjects show several clinical manifestations such as sarcopenia, dynapenia, fatigue, sedentary lifestyle, malnutrition, cognitive decline and disability in activities of daily life. Frailty is a typically unstable condition, which can be aggravated by a multitude of triggers of clinical (disease, trauma, etc) and psychosocial (life events) origin.
The aims of FRIA's research activities are to untangle the underlying mechanisms and to develop interventions for prevention and rehabilitation of frailty in the aged.