The regulation of muscle atrophy by enzymes of the ubiquitin-proteasome system

肌肉萎缩是对许多常见疾病的致残反应，包括感染，癌症和糖尿病，由蛋白质分解的快速增加驱动。这种消耗在肺部疾病中尤其重要，其中胸部肌肉的虚弱可能严重影响患者的长期生存。此外，几种情况可能同时发生，如类固醇治疗和不动，这进一步增加了肌肉萎缩的严重程度。据确定，这种快速的蛋白质分解主要是由“泛素系统”的激活引起的。泛素是一种附着在其他蛋白质上的小分子，发出破坏它们的信号，最近的研究表明，泛素系统的几种酶在肌肉萎缩中增加。泛素系统由去泛素化酶（DUBs）调节，其从蛋白质中去除泛素。到目前为止，DUB在肌肉分解中的确切作用仍有待确定。在这个项目中，我将研究DUBs在肌肉萎缩中的作用，并研究蛋白质分解的不同原因如何结合联合收割机引起严重的肌肉损失。特别是，我将研究DUBs如何影响泛素水平，并测量哪些基因在肌肉分解中被激活。这些研究将为肌肉萎缩是如何刺激和调节的提供重要的见解。

Muscle wasting is a disabling response to many common conditions, including infections, cancer and diabetes, driven by a rapid increase in protein breakdown. This wasting is particularly important in lung diseases, where weakness of the chest muscles may severely affect patients‘ longterm survival. In addition, several conditions may occur simultaneously, such as steroid treatment and immobility, which further increase the severity of muscle wasting. It is established that this rapid protein breakdown is mainly caused by activation of the ‘ubiquitin system‘. Ubiquitin is a small molecule that attaches to other proteins, signalling their destruction, and recent research has shown that several enzymes of the ubiquitin system are increased in muscle wasting. The ubiquitin system is regulated by deubiquitinating enzymes (DUBs), which remove ubiquitin from proteins. So far, the precise role of DUBs in muscle breakdown remains to be determined. In this project, I will study the function of DUBs in muscle wasting, and examine how different causes of protein breakdown combine to induce severe muscle loss. In particular, I will study how DUBs affect ubiquitin levels, and measure which genes are activated in muscle breakdown. These investigations will provide essential insights into how muscle wasting is stimulated and regulated.