New antiadipogenic drugs to reduce fibroadipogenic precursor cell differentiation process in DMD

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Muscle degeneration in Duchenne muscular dystrophy (DMD) is characterized by loss of muscle fibers and its replacement by fat and fibrotic tissue. Fibro-adipogenic progenitors (FAPs), a type of skeletal muscle resident mesenchymal stem cells, are the main cause of fibro-fatty expansion. The molecular pathways driving the differentiation of human FAPs to adipocytes remain unexplored. Recent studies have highlighted the role of Wnt/Hedgehog/Notch pathway in the regulation of FAP differentiation to adipocytes and can be promising targets to mitigate the detrimental effects of intramuscular fat infiltrations in muscular dystrophies. This project focus to unravel and target the molecular pathways that are differentially modulated in DMD FAPs compared to control FAPs. Based on the preliminary screening of 187 small molecules from the Wnt/Hedgehog/Notch compound library previously performed in our lab, I hypothesise that the shortlisted molecules, Bruceine D, RGB (free base) and GSK 3-inhibitor 1, can effectively decrease FAPs proliferation and differentiation into adipogenic lineage, thereby reducing the degenerative process of fibro-fatty infiltration in muscular dystrophies. The key objectives of the study are: - To identify antiadipogenic drugs that can efficiently reverse FAPs adipogenic differentiation process in vitro and in vivo- To identify the effect of candidate drugs on epigenetic factors in vitro- To identify the molecular mechanism underlying the antiadipogenic effect of candidate drugs in vitro Accomplishing these aims will allow us to identify effective therapies that could be used to reduce fibro-fatty infiltration in patients with DMD and will provide new insights into molecular and epigenetic regulation of FAPs differentiation to adipocytes. The project aligns with many of the priorities of the BBSRC. The project will help to understand the process of muscle degeneration that takes place in patients with muscular dystrophies using human cells and muscle samples. This will provide valuable information about the molecules that regulate DMD progression but also help to understand the differences among individuals, therefore aligning with the ''Biosciences for an integrated understanding of health'' objective. Three research groups with different expertise will work in this project using new technologies such as transcriptomics, epigenomics, bioinformatic analysis or 3D cell culture in line with the ''transformative technologies'' strategy. This project will foster more collaboration between the groups and will open the door to collaborations with industrial partners with the aim to test the therapies in clinical trials.