Investigating the role of PERM1 in transcriptional regulation of oxidative metabolism, in Duchenne Muscular Dystrophy.

This project has been approved for funding - the activation procedure is still pending

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2023

In patients affected by Duchenne dystrophy, the muscle displays a reduced mitochondria function. Studies in the mouse model of DMD indicate that restoration of mitochondrial metabolism improves the dystrophic muscle, and approaches aimed at correcting mitochondrial functions may represent an adjuvant therapy for Duchenne.
In this project, we propose to study a protein that decreases in Duchenne and that is involved in the expression of genes that enable proper mitochondrial function, the PERM1 protein. In particular, PERM1 performs its regulatory function through interactions with a well-known and important coactivator of mitochondrial genes, PGC-1α. We will therefore study their interaction in the nucleus, using microscopy techniques. We hypothesize that PERM1 and PGC-1α form domains where they reach a higher concentration compared to the rest of the nucleus, and that these nucleation points are particularly relevant for the activation of mitochondrial genes. We will use the mouse model of Duchenne dystrophy, the mdx mouse, to study the effect of PERM1 re- expression in muscle, and its impact on mitochondrial function. In parallel, we will also employ immortalized cells derived from Duchenne patients to validate our results in a human model. We also propose to study the regions of the genome that are recognized by PERM1 and PGC-1α, to define the genes controlled by these two regulators. Overall, this study aims to characterize the mechanisms by which PERM1 regulates mitochondrial function and its role in Duchenne dystrophy.