Description du projet
Une nouvelle frontière dans la recherche sur l’inflammation
L’inflammation est une réaction défensive de l’organisme déclenchée lorsque des agents infectieux étrangers sont détectés ou en réponse à des lésions tissulaires. Cependant, certaines maladies graves, comme la neurodégénérescence, l’athérosclérose, le diabète ou le cancer, sont liées à une inflammation chronique à long terme induite par le stress et qui se produit en réponse au stress cellulaire provoqué par des perturbations de la physiologie normale. Malheureusement, les capteurs et effecteurs cruciaux de l’inflammation induite par le stress restent un mystère. Le projet DESTRESS, financé par l’UE, étudiera le rôle et le comportement des récepteurs dits de mort cellulaire, membres de la famille des récepteurs du facteur de nécrose tumorale, en tant qu’intégrateurs de l’inflammation induite par le stress pour dévoiler la composition de leurs complexes de signalisation, faire évoluer la recherche et permettre le traitement de nombreuses maladies liées au stress cellulaire.
Objectif
Inflammation is initiated in response to the detection of foreign entities, called PAMPs derived from infectious agents, or due to the release of intracellular contents, called DAMPs, due to serious tissue damage (i.e. necrosis). However, inflammation can also be initiated in response to Cell Stress (e.g. ER stress, cytoplasmic stress, mitochondrial stress) resulting from perturbations in normal physiology, but how cellular stress is converted to inflammatory outputs is very poorly understood. Many diseases are associated with chronic long-term inflammation (e.g. cancer, obesity, neurodegeneration, diabetes), which is a compounding factor in these conditions that can accelerate disease progression, but the inflammation seen in these conditions does not have an obvious infectious (PAMP) or acute injury (DAMP) cause. Instead, these diseases are frequently associated with persistent cell/tissue stress (e.g. due to misfolded proteins, elevated dietary fats, or metabolic stress) arising from persistent ER or cytoplasmic stress, that is likely to serve as a key driver of inflammation in these settings. However, the key sensors and effectors of stress-induced inflammation remain enigmatic.
Based on our recent observations, I wish to explore the hypothesis that members of the 'Death Receptor' subset of the TNF receptor family serve as stress-associated molecular patterns (SAMPs), becoming upregulated and/or activated in response to divergent forms of ER and cytoplasmic stress, leading to inflammation. Here, we will explore the role of Death Receptors as putative SAMPs, how they are activated by stress, the composition of their stress-induced signaling complexes, and the potential to suppress stress-induced inflammation through targeting these receptors. Understanding how Cell Stress initiates inflammation will open up a new frontier in inflammation research and identify new molecular targets for the treatment of chronic inflammation associated with multiple diseases.
Champ scientifique
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
D02 CX56 DUBLIN 2
Irlande