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Financement britannique (846 540 £) : FAP-DMD : Élucider le rôle des cellules FAP dans le processus de dégénérescence musculaire chez les patients atteints de dystrophie musculaire de Duchenne Ukri 01/03/2022 Recherche et innovation du Royaume-Uni, Royaume Uni
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FAP-DMD : Élucider le rôle des cellules FAP dans le processus de dégénérescence musculaire chez les patients atteints de dystrophie musculaire de Duchenne
| Abstract | Duchenne muscular dystrophy (DMD) is a devastating disease produced by mutations in the dystrophin gene. Disease's onset with onset of weakness occurs before the age of 5 years and progresses leading to loose of ambulation during adolescence. Patients die during the third decade of life because of cardiac or respiratory complications. The only treatment approved so far is corticoids that slow down progression but without having a real impact in natural history. Despite huge efforts invested in developing new treatments, most of them have failed. At the moment, gene therapies based on the release of a healthy copy of the dystrophin gene to the muscle fibers are showing promising results, but it seems clear that they are not going to be able to stop disease's progression and that the process of muscle degeneration will remain active. The process of muscle degeneration in DMD has been studied for many years in animal models of the disease. Lack of dystrophin makes the fibers more susceptible to damage during normal muscle contraction. Damaged fibers are initially repaired by cells named satellite cells. However, repetitive damage triggers a series of consequences in the tissue including persistent infiltration by inflammatory cells that activates a type of cell known as fibro-adipogenic precursor cells (FAPs). FAPs contribute to muscle degeneration as they produce fat and fibrotic tissue which substitutes the damaged muscle fibers. During disease's progression, loss of fibers is associated to expansion of fibrotic and fatty tissue which impairs the capability of satellite cells to regenerate damaged muscle fibers. Although several molecules have been identified as key to regulate this process in mice, little is known in humans what is limiting the development of new treatments. We have developed a new protocol to isolate satellite cells and FAPs from muscle biopsies that were taken for diagnosis and are stored in biobanks. We have analyzed the cells obtained from DMD and healthy people and have identified different types of FAP cells. To summarize we have identified two main populations, one that is actively proliferating and retain stemness properties and another that is already committed to produce fibrotic tissue. In this proposal we will explore when these different populations appear in the progression of DMD patients using muscle biopsies of patients at different clinical stages and correlate their presence with tissue features to understand if these subpopulations are associated to changes such as fibrosis, inflammation or muscle fiber death. Then we will analyze the genes that are expressed in control and DMD muscle by fibers but also by other components, such as inflammatory cells, that could guide the changes in FAP subtype. Understanding the molecular pathways governing the changes in FAP subpopulations will provide potential new targets for therapies aimed to counteract the expansion of fibro-fatty tissue. In a third stage we will isolate the subpopulations of FAPs and study their properties including how they proliferate, move, or differentiate into fibrotic or fat producing cells and how they interact with satellite cells. These later studies provide information about how two cells interact in a dish, as it would happen when they are in the tissue. We will study this interaction both in standard 2D culture dishes, but also in 3D systems using printed molds that enable a more perdurable and structured generation of artificial muscles. These experiments will provide valuable information to understand if and how FAPs influence satellite cell function. Finally, we will test libraries of drugs able to counteract the function of key molecular pathways identified in the previous experiments to understand if they are able to modulate the function of FAPs. |
| Category | Research Grant |
| Reference | MR/W019086/1 |
| Status | Closed |
| Funded period start | 01/03/2022 |
| Funded period end | 31/08/2025 |
| Funded value | £846 540,00 |
| Source | https://gtr.ukri.org/projects?ref=MR%2FW019086%2F1 |
Participating Organisations
| Newcastle University | |
| Institute of Myology | |
| Leiden University | |
| Institute for Bioengineering of Catalonia | |
| Binghamton University | |
| University College London | |
| Hospital Sant Joan de Deu | |
| Royal Institute of Technology |
Cette annonce se réfère à une date antérieure et ne reflète pas nécessairement l’état actuel. L’état actuel est présenté à la page suivante : Newcastle University, Newcastle Upon Tyne, Royaume Uni.
