Project description DEENESFRITPL Inflammation control by promyelocytic leukaemia protein Promyelocytic leukaemia protein (PML) is is a tumour suppressor protein required for the assembly of nuclear structures, called PML-nuclear bodies, which are formed amongst the chromatin of the cell nucleus. PML mutations and the subsequent dysregulation has been implicated in a variety of cancers. The EU-funded InflaPML project proposes that several neuroinflammatory diseases can be linked through a common molecular pathway, whose molecular components could be targeted for therapy. Researchers propose a new mechanism involving IL-1β regulation. Specifically, they hypothesise that PML has an additional role outside the tumour environment, acting at the endoplasmic reticulum-mitochondria interfaces as a modulator of NLRP3, or cryopyrin, a protein expressed in macrophages as a component of the inflammasome. The ultimate goal of the project is to develop drugs targeting a PML-associated pathway for treatment of neuroinflammatory diseases. Show the project objective Hide the project objective Objective 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. Fields of science medical and health sciencesbasic medicineneurologyepilepsymedical and health sciencesbasic medicineimmunologymedical and health sciencesbasic medicinepathologymedical and health sciencesbasic medicineneurologystrokemedical and health sciencesclinical medicineoncologyleukemia Keywords Inflammation NLRP3 inflammasome mitochondria-associated membranes Promyelocytic leukemia protein (PML) Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-STG - ERC Starting Grant Call for proposal ERC-2019-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Coordinator UNIVERSITA DEGLI STUDI DI FERRARA Net EU contribution € 1 462 500,00 Address Via ariosto 35 44121 Ferrara Italy See on map Region Nord-Est Emilia-Romagna Ferrara Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITA DEGLI STUDI DI FERRARA Italy Net EU contribution € 1 462 500,00 Address Via ariosto 35 44121 Ferrara See on map Region Nord-Est Emilia-Romagna Ferrara Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
