经典瞬时感受器电位通道(TRPC)在哮喘气道平滑肌细胞增殖中的作用及其机制研究

Bronchial asthma is a common disease that seriously threatens to human health and its morbidity and mortality is increasing year by year. However, we can only control the symptoms of asthma currently because little is known about the pathogenesis of asthma. Therefore, it becomes the focus nowadays that further clarifying the pathogenesis and searching for directed-treatment of asthma. Asthma is characterized by airway remodeling which is the pathological basis of irreversible airflow obstruction. Airway smooth muscle cells (ASMCs) is the predominant part of airway wall and its proliferation is involved in airway remodeling. Canonical transient receptor potential channel (TRPC) is an important signal transduction pathway on cell membrane, contributing to cell proliferation and differentiation. Studies have reported that TRPC is implicated in bronchoconstriction, activation of the transcription factor and proliferation of ASMCs. However, it is important to mention that very few studies have investigated the role of TPRC on proliferation of ASMCs. This subject based on our previous study is to investigate the role of TPRC on proliferation of airway smooth muscle cells in asthma, thus providing evidences about mechanism of proliferation of airway smooth muscle cells and seeking out a new target of airway remodeling in asthma.

支气管哮喘是一种严重危害人类健康的常见疾病，其发病率和死亡率逐年上升。由于哮喘的发病机制尚未明确，目前的治疗只能达到症状的控制。因此，进一步明确哮喘的发病机制、寻找更有针对性的治疗方法是目前国内外研究的热点。气道重塑是哮喘的重要病理特征，是哮喘不可逆气流阻塞的病理基础。气道平滑肌细胞作为气道壁的主要组成成分，其增殖是气道重塑的重要原因之一。经典瞬时感受器电位通道(TRPC)是细胞膜上重要的信号传导通路，对细胞的增殖、分化起着关键作用。有研究发现，TRPC对支气管收缩、转录因子的活化、平滑肌细胞的增殖等有重要的影响。但TRPC是否参与了气道平滑肌细胞的增殖调控，目前国内外均尚未见文献报道。故本课题旨在我们研究的基础上，进一步探讨TRPC在哮喘气道平滑肌细胞增殖中的作用，从而为阐明哮喘气道平滑肌细胞增殖的机制，以及为临床上寻找治疗哮喘气道重塑新的靶点提供重要的科学依据。

研究证实经典瞬时感受器电位通道(TRPC)蛋白在血管平滑肌细胞、内皮细胞和肿瘤细胞增殖调节中发挥着至关重要的作用，但在以气道平滑肌细胞（ASMCs）增殖为主的哮喘气道重塑中的表达和对ASMCs增殖的作用尚未可知。本研究检测了哮喘模型大鼠的ASMCs中TRPC1的表达情况，并采用分子生物学方法研究了ASMCs中TRPC1的上游调节分子机制，即探究受lncRNAs BCYRN1和miR-135a调控的TRPC1在ASMCs增殖和迁移中的作用。结果表明，一方面，lncRNAs BCYRN1可通过稳定TRPC1蛋白造成哮喘大鼠支气管平滑肌细胞增殖和迁移；另一方面，miR-135a可通过抑制TRPC1表达抑制支气管平滑肌细胞增殖，且该通路在Schisandrin B发挥抑制支气管平滑肌细胞增殖中具有重要作用。本项目的完成有助于理解TRPC1在哮喘气道平滑肌细胞增殖中的作用，为临床上寻找治疗哮喘气道重塑新的靶点提供重要的科学依据。