TELETHON GSA21A002 - Identificazione di nuovi bersagli molecolari per la fibrodisplasia ossificante progressiva (FOP): la via autofagica è coinvolta? (DSB.AD006.334)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of molecular biology and pathology (IBPM)

Project manager

VENTURINA STAGNI
Phone number: 06499338373
Email: venturina.stagni@cnr.it

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a hereditary form of heterotopic ossification (HO). FOP is due to a heterozygous mutation in the ACVR1 gene that lead to constitutive activation of mutant ACVR1, involved in HO. Hypoxia environment is crucial in the induction of HO in FOP and sustains mutant ACVR1 constitutive signalling. Despite this, the molecular mechanism involved in adaptation to hypoxia environment and that contribute to mutant ACVR1 signalling in FOP are still largely unknown. In this project, we hypothesize that autophagy signalling, could be involved in hypoxia induction of HO and in sustaining mutant ACRV1 signalling. This study could contribute to find new molecular "actors" involved in FOP progression, and so could lead to the design new molecular target therapy for FOP.

Goals

Based on literature and our previously works, we hypothesize that mutant ACVR1 in Fibrodysplasia ossificans progressiva (FOP) could promote heterotopic ossification (HO) through autophagy signalling pathway under hypoxic condition. We further reasoned that molecular oxygen sensor ATM kinase could connect hypoxia to autophagy, through ATG4C regulation, and that activation of this axis could be essential in maintaining FOP chondrocyte homeostasis in hypoxic environment. If our hypothesis is true, the molecular targeting on this "addicted" pathway could restore BMP signalling to normal levels in FOP cells and abrogated HO. To explore these hypotheses, we propose two main AIMS:
- AIM 1: To investigate how modulation of autophagy and ATM-ATG4C axis could impact on ACVR1 signalling and FOP chondrocyte differentiation;
- AIM 2: To set up a model system to study auopthagic flux in FOP chondrocyte

Start date of activity

23/09/2021

Keywords

autofagia, Fibrodysplasia ossificans progressiva (FOP), ipossia

Last update: 19/05/2025