TRAF6在蛛网膜下腔出血后早期脑损伤中的作用及机制研究

蛛网膜下腔出血（SAH）后早期脑损伤（EBI）是影响患者预后的主要因素，其内在机制尚不够清晰。申请人前期研究提示免疫炎症、氧化应激和自噬等过程在EBI发生中起重要作用。肿瘤坏死因子受体相关因子6（TRAF6）在体内分布广泛，在免疫、细胞因子产生、炎症和氧化应激反应、自噬等过程中起重要作用。我们的预实验提示TRAF6在SAH后过度活化，在EBI的发生中起重要作用，但具体机制有待明确。我们提出假说：TRAF6可能通过影响炎症和氧化应激反应、自噬等信号通路，导致EBI的发生。为验证这一假说，我们将通过大鼠离体和在体SAH模型，采用基因过表达、RNA干扰和抑制剂等手段，多角度验证TRAF6在EBI发生中的作用方式及调控机制。本研究将从TRAF6蛋白这个新视点为揭示SAH后EBI的发生机制奠定基础，为临床治疗SAH后EBI的防治提供新的思路。

Early brain injury (EBI) after subarachnoid hemorrhage(SAH) is the main factor that leads to the poor outcome of the patient, however, the exact mechanism still remans unclear. Previous researches of applicant’s suggested that the immune inflammatory, oxidative stress reaction and autophagy play an important role in the occurrence of EBI. TNF receptor-associated factor 6（TRAF6）has wide tissue distribution, with highest levels in brain, lung, liver, skeletal muscle and kidney. TRAF6, which serves as a key regulator, is involved in the signals regulating the adaptive and innate immunity, cell survival, cellular proliferation, cytokine production, inflammatory and oxidative stress reaction, and autophagy. Preliminary studies conducted by the applicant’s group suggested that the enhanced expression of TRAF6 was detected in the cortex after SAH which may play an important role involving in the pathogenesis of EBI after SAH. However, the exact role of TRAF6 remains unclear. Therefore, we hypothesis that TRAF6 plays the role in the pathogenesis of EBI after SAH by involving in the signals of inflammatory and oxidative stress reaction, and autophagy. To testify our hypothesis, we intend to establish SAH models in vitro and in vivo to investigate the exact role and mechanisms of TRAF6 in the pathogenesis of EBI after SAH by means of Western blot, real time PCR, EMSA, plasmid vector transfection, gene over expression and gene silencing, etc. The findings of this study will not only academically clarify the the pathogenesis of EBI caused by SAH based on TRAF6, but also provide a strong academic foundation for making a breakthrough in clinical treatment.