HuR调控转录因子EB在骨性关节炎中的作用机制研究

骨性关节炎（OA）尚无延缓或逆转其进展的有效干预措施，主要原因是其病理机制不清。氧化应激是OA主要病理特征之一，课题组前期报道氧化应激通过抑制转录因子EB（TFEB）表达导致自噬流阻滞，但具体机制不清。课题组通过OA软骨RNA-seq筛选出RNA结合蛋白HuR，发现 OA软骨组织及氧化应激作用下软骨细胞的HuR低表达，预实验提示HuR与TFEB表达及自噬流相关，但HuR调控TFEB的机制及其在OA病理过程中的作用未知。我们假设：氧化应激通过HuR抑制TFEB的表达导致软骨细胞自噬流阻滞，HuR可作为OA治疗靶点。本课题拟：1.过表达及敲降HuR，检测氧化应激条件下软骨细胞的功能；2.从HuR调控TFEB角度阐释作用机制；3.利用HuR过表达病毒，体内检测其对OA病理的修复作用。本研究从RNA结合蛋白HuR调控TFEB角度阐释OA疾病中自噬流阻滞新机制，可为OA治疗提供新靶点。

Due to its pathological mechanism is unclear, osteoarthritis (OA) has no effective interventions to delay or reverse its progression. Oxidative stress is the main pathological feature of OA, our research team has reported that oxidative stress can lead to blockage of autophagic flux by inhibiting transcription factor EB (TFEB) expression in chondrocytes, but the specific mechanism is unclear. Our research team identified the RNA-binding protein HuR by using OA articular cartilage RNA-sequencing, and down-regulation of HuR in OA cartilage tissue as well as in tert-butyl hydroperoxide (TBHP)-treated chondrocytes. We also confirmed that HuR was correlated to the TFEB expression and autophagic flux, but the mechanism of HuR regulates TFEB and its role in OA pathology is unknown. We hypothesized that oxidative stress inhibits the expression of TFEB by HuR which can lead to blockage of autophagic flow in chondrocytes, and HuR can be used as a therapeutic target in OA. We will carry out the following studies to prove our hypothesis. Firstly, we detect the role of HuR using over-expression or knock-down viruses; Secondly, explaining the mechanism of regulation of TFEB by HuR; Finally, we will use HuR overexpressing virus to treat OA in mice. This study will help to clarify the mechanism of RNA binding protein HuR in OA, and also will provides new targets for its treatment.