去泛素化修饰RORγt调控Th17细胞功能的机理研究

Th17 is a recently identified Th subset, which is a promoter of the inflammatory response. The differentiation of Th17 plays a critical role in the development of autoimmune diseases, such as rheumatic heart disease (RHD). The orphan nuclear receptor RORgammat (RORγt) is crucial for Th17 development but the modulation of its stability remains uncharacterized. ..Protein ubiquitination modification plays a critical role in the immune cell lineage differentiation and function. Currently, several deubiquitinases (DUBs) or E3 ligases have been found as important regulators of Th17 cell differentiation. We focus on the deubiquitination of RORγt...Our preliminary work revealed that Th17 cells highly express deubiquitinase USP4 which is essential for maintaining RORγt and Th17 function. On the basis of our previous study, we will further analyze the mechanism underlying how ubiquitination and deubiquitination affects RORγt stability and activity, as well as how the modifications are involved in Th17 cell function..This study will lay a basis on the better understanding of RORγt mediated transcription regulation and provide new clues for the treatment of important human diseases.

Th17细胞是一类介导炎症反应的淋巴细胞。Th17细胞在对抗特定病原体的宿主免疫中发挥功能，能够清除一些胞外病原体。同时，在自身免疫疾病的发生发展中，也起到重要作用。Th17分化中关键性的转录因子是RORγt，对于Th17细胞的分化和功能至关重要。.泛素化是一种广泛存在而且至关重要的翻译后修饰，是机体调节细胞内蛋白水平与功能的一个重要机制。近年来的研究也证实，泛素化与去泛素化能够调节T细胞的分化，从而影响免疫系统的活性。因此，我们设想Th17细胞至关重要的转录因子RORγt也会受到泛素化的调节。.我们前期的实验已经证实去泛素化酶USP4可以去泛素化并且稳定RORγt，促进Th17细胞的分化。本项目申请将进一步分析去泛素化酶USP4对于RORγt、 Th17细胞以及免疫系统的影响，并且为进一步理解RORγt 介导的转录调节机制打下分子基础，从而为人类免疫相关疾病的治疗提供新的线索。

泛素化，作为一种广泛存在而且至关重要的翻译后修饰，是机体调节细胞内蛋白水平与功能的一个重要机制，在正常和疾病状态下调节一系列重要的细胞进程。我们的前期研究证实Th17细胞的关键转录因子RORγt受到去泛素化酶USP4的调控。在本项目的资助下，我们深入分析了去泛素化酶USP4对于Th17细胞分化、功能的促进作用。并且在体内证实USP4的抑制剂可以在自身免疫性疾病模型中抑制炎症进展。我们所发现的调控机制及抑制剂为自身免疫疾病的治疗提供了新的靶点和药物前体化合物。此外，我们也分析了在甲状腺相关眼病患者体内过度激活的Th17参与的致病机制，为寻找新的诊疗策略做出积极的贡献。