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

杜氏肌营养不良症（DMD）的肌肉变性的特征是肌纤维的损失和脂肪和纤维化组织的替代。成纤维脂肪祖细胞（FAPs）是骨骼肌中的一种间充质干细胞，是导致纤维脂肪扩张的主要原因。驱动人FAP分化为脂肪细胞的分子途径仍然未被探索。最近的研究强调了Wnt/Hedgehog/Notch通路在FAP向脂肪细胞分化的调节中的作用，并且可以成为减轻肌营养不良症中肌内脂肪浸润的有害影响的有希望的靶点。该项目的重点是解开和目标的分子途径，差异调制DMD FAP相比，控制FAP。基于本实验室先前从Wnt/Hedgehog/Notch化合物文库中初步筛选的187个小分子，我假设入围分子Bruceine D、RGB（游离碱）和GSK 3-inhibitor 1可以有效地减少FAP增殖和向成脂谱系分化，从而减少肌营养不良症中纤维脂肪浸润的退行性过程。该研究的主要目标是：- 鉴定能够在体外和体内有效逆转FAP成脂分化过程的抗成脂药物-鉴定候选药物对体外表观遗传因子的作用-鉴定候选药物体外抗成脂作用的分子机制实现这些目标将使我们能够鉴定可用于减少FAP成脂分化的有效疗法。DMD患者的脂肪浸润，并将提供新的见解的分子和表观遗传调控FAP分化为脂肪细胞。该项目符合BBSRC的许多优先事项。该项目将有助于了解使用人体细胞和肌肉样本在肌肉萎缩症患者中发生的肌肉退化过程。这将提供有关调节DMD进展的分子的有价值的信息，但也有助于了解个体之间的差异，因此与“生物科学对健康的综合理解”目标保持一致。三个具有不同专业知识的研究小组将在该项目中使用新技术，如转录组学，表观基因组学，生物信息学分析或3D细胞培养，以符合“变革技术”战略。该项目将促进这些团体之间的更多合作，并将为与工业合作伙伴的合作打开大门，旨在在临床试验中测试这些疗法。

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.