Descrizione del progetto
Controllo dell’infiammazione da parte della proteina della leucemia promielocitica
La proteina della leucemia promielocitica (PML, ProMyelocytic Leukaemia) è una proteina soppressore tumorale necessaria per assemblare le strutture nucleari, denominate corpi PML-nucleari, le quali vengono costituite all’interno della cromatina del nucleo cellulare. Le mutazioni della PML e la successiva disregolazione sono state coinvolte in moltissimi tumori. Dal progetto InflaPML, finanziato dall’UE, è emerso che diverse malattie neuroinfiammatorie possono essere collegate tramite una via molecolare diffusa, i cui componenti molecolari potrebbero essere mirati per la terapia. I ricercatori hanno suggerito un nuovo meccanismo che coinvolge la regolazione delle IL-1β; precisamente, essi ipotizzano che la PML svolga un ruolo aggiuntivo al di fuori dell’ambiente tumorale, agendo sulle interfacce del reticolo endoplasmatico-mitocondri come un modulatore di NLRP3, o criopirina, una proteina espressa in macrofagi come un componente dell’inflammasoma. L’obiettivo finale del progetto consiste nello sviluppare farmaci intervenendo su una via PML-associata per il trattamento di malattie neuroinfiammatorie.
Obiettivo
Local sterile inflammation arise in many pathologic states, including several diseases of the nervous system as brain stroke, neurodegenerative diseases and epilepsy. The persistent and de-regulated inflammatory response sustains these neurological pathologies worsening their prognosis. Different molecular players, as NLRP3 and P2X7 have been shown to contribute to the progression of these illnesses triggering the release of IL-1β and recruiting cellular components of the immune response at the neurodegeneration site. Consistently, brain penetrant P2X7 antagonists are clinically used to treat epilepsy and neurodegenerative diseases, while the pharmacological modulation of IL-1β is still unsuccessful. Unfortunately, the molecular mechanism underlying neuroinflammation and NLRP3 inflammasome assembly remains elusive. Here we propose that different neuroinflammatory diseases can be linked together in a common disease pathway, of which damaged function should be targeted for therapy. Specifically we propose a new mechanism acting on IL-1β regulation: we hypothesize the existence of a new activity of PML outside tumour environment, acting at the endoplasmic reticulum-mitochondria interfaces (MAMs) as modulator of NLRP3 inflammasome. On these bases, I propose a project in which PML activity at MAMs can be the key link of different neuroinflammatory diseases. Our goals are as follow: 1) to demonstrate that PML post-transcriptionally controls NLRP3 activity at the ER/MAMs compartments and thus IL-1β release via P2X7; 2) to prove that IL-1β release have a strong influence on neuronal environment and survival, and might represent a prognostic factor; 3) to develop new drugs targeting PML/NLRP3/P2X7 axis to overcome the unexpected failure of anti-IL-1 therapies.
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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
44121 Ferrara
Italia