ASIC1a调控自噬介导的LaminB1蛋白降解在骨关节炎软骨细胞衰老中的作用及其机制

软骨细胞衰老是启动骨关节炎（OA）关节软骨退变的始动因素之一。酸敏感离子通道1a（ASIC1a）属于DEG/ENaC超家族一员，H+激活可介导Ca2+内流，参与组织酸化等病理过程。我们前期研究表明组织酸化微环境可诱发OA关节软骨细胞衰老，并发现酸激活ASIC1a介导的自噬及Lamin B1降解对其有调控作用。我们推测ASIC1a可通过自噬途径介导Lamin B1降解来促进OA软骨退变。本研究拟在软骨细胞中通过ASIC1a激活剂或阻滞剂、自噬抑制剂或激活剂、RNA干扰及转录组测序等方法，分析ASIC1a介导的自噬在酸诱导的关节软骨细胞衰老中的作用；通过对自噬和泛素蛋白酶体降解途径的激活与抑制，分析衰老关键蛋白Lamin B1降解在ASIC1a介导软骨细胞衰老中的作用；最后，通过动物模型进一步验证，初步阐明ASIC1a调控OA关节软骨细胞衰老的作用及其机制，为OA的防治提供新的理论依据及靶点。

Chondrocyte senescence is one of the initiating factors that initiate the degeneration of articular cartilage in osteoarthritis (OA). Acid-sensitive ion channel 1a (ASIC1a) belongs to the DEG/ENaC superfamily. Activation of ASIC1a by extracellular acidification can mediate Ca2+ influx and participate in pathological processes such as tissue acidification. Our previous studies have showed that tissue acidification microenvironment can induce OA articular chondrocyte senescence, and found that acid-activated ASIC1a-mediated autophagy and Lamin B1 degradation have a regulatory effect on acid-induced chondrocyte senescence. We speculate that ASIC1a may mediate Lamin B1 degradation through autophagy to promote OA cartilage degeneration. This study intends to analyze the role of ASIC1a-mediated autophagy in acid-induced senescence of articular chondrocytes through ASIC1a activator or blocker, autophagy inhibitor or activator, RNA interference and transcriptome sequencing. Secondly, the role of aging key protein Lamin B1 degradation in ASIC1a-mediated senescence were analyzed in chondrocytes through the activation and inhibition of autophagy and ubiquitin proteasome degradation pathways. Finally, this regulatory role were further verificated using animal model. The effects and mechanisms of ASIC1a on articular chondrocyte-senescence in osteoarthritis were preliminary clarified, and which providing a new theoretical basis and target for the prevention and treatment of OA.