神经元自噬调控NLRP1炎性小体在蛛网膜下腔出血后早期脑损伤中的机制研究

蛛网膜下腔出血（SAH）是一种严重危害健康的疾病，它引发的早期脑损伤是其首要的致病机制，但目前仍缺乏有效的干预手段。自噬是细胞内溶酶体依赖的物质降解过程，它对维持细胞自稳态、应对内外环境刺激具有重要意义。我们前期研究发现，自噬激活对SAH后早期脑损伤发挥着显著的神经保护作用，但其具体作用机制尚不明确。炎性小体介导的炎性反应广泛参与众多神经系统疾病的发生发展，但尚未有报道其与SAH后神经元自噬间的联系。我们最新研究发现，SAH后神经元自噬可显著调控NLRP1炎性小体活性水平，阻断NLRP1将显著削弱自噬的神经保护作用。因此我们将围绕神经元自噬-NLRP1炎性小体通路，利用SAH模型大鼠、原代神经元细胞及成熟的神经元细胞系，采用免疫印迹、RNA干扰、CRISPR/CAS9等技术，从体内、体外两个层面，阐明神经元自噬缓解SAH后早期脑损伤的具体作用机制，为临床治疗SAH提供新思路和理论依据。

Subarachnoid hemorrhage(SAH) is a devastating disease with high mortality and significant morbidity among patients. Early brain injury following SAH is considered as the primary cause of poor outcome after SAH and remains no effective therapy. Autophagy is a homeostatic process that involves the sequestration of cytoplasmic components in double-membraned autophagosomes. Autophagy acts as a survival mechanism under conditions of stress, maintaining cellular integrity by regenerating metabolic precursors and clearing subcellular debris. Our previous study have demonstrated that autophagy activation is associated with neuroprotection against apoptosis in a rat model of SAH. However, the exact molecular mechanism of that still remains obscure. Inflammasomes are essentail protein complexes which have been implacated in a arrange of neurological diseases, but whether and how inflammasomes are involved in the process of autophagy after SAH remains unknown. Our preliminary inspections showed that NLRP1 inflammasome was significantly regulated by autophagy in SAH rat model, and blocking NLRP1 could significantly attenuate the neuroprotection provided by autophagy. This study was undertaken to investigate the role and the mechanisms of autophagy-NLRP1 pathway in early brain injury following SAH in both animal and cellular levels, and thus to provide a new target for SAH treatment.