Descrizione del progetto
Una nuova frontiera nella ricerca sulle infiammazioni
L’infiammazione è una reazione di difesa dell’organismo dovuta al rilevamento di agenti infettivi estranei o all’effetto di un danno tissutale. Alcune malattie gravi come la neurodegenerazione, l’aterosclerosi, il diabete e il cancro sono però legate a un’infiammazione cronica a lungo termine indotta dallo stress, che si verifica come risposta allo stress cellulare provocato da perturbazioni della normale fisiologia. Purtroppo, i sensori e gli effettori cruciali dell’infiammazione indotta dallo stress rimangono un mistero. Il progetto DESTRESS, finanziato dall’UE, esplorerà il ruolo e il comportamento dei cosiddetti recettori di morte, membri della famiglia dei recettori del fattore di necrosi tumorale, come integratori dell’infiammazione indotta dallo stress per svelare la composizione dei loro complessi di segnalazione, spostare la ricerca e permettere un trattamento efficace di numerose malattie associate allo stress cellulare.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
D02 CX56 DUBLIN 2
Irlanda