PTEN调控CD38介导的钙信号振荡抑制哮喘气道重塑的分子机制

气道重塑在哮喘的发生发展中起重要作用。气道平滑肌细胞钙离子内流紊乱所致的钙振荡节律失调与之密切相关。课题组在发现PTEN缺失促进哮喘小鼠气道重塑，引起平滑肌细胞内钙离子增加和钙信号调制分子CD38变化的基础上，针对PTEN对钙信号调控机制不清的现状，提出PTEN调控CD38介导的钙振荡影响气道重塑的新设想。本研究利用PTEN条件敲除小鼠和气道平滑肌细胞模型，运用免疫细胞和分子生物学技术，观察PTEN对平滑肌细胞钙离子流、钙信号振荡及气道重塑的影响，揭示PTEN对PI3K/AKT通路的抑制效应及PTEN-CD38相互作用在CD38表达和活性调控中的作用，阐明PTEN-CD38-钙振荡-气道重塑的调控路径和机制，运用信号通路抑制剂比较研究其作用差异，旨在确证PTEN调控CD38介导的钙信号振荡在抑制哮喘气道重塑中的作用并阐明机制，为哮喘气道重塑信号调控提供新通道，为哮喘的精准治疗提供新靶点。

Airway remodeling plays critical roles in the initiation and progression of asthma. Calcium influx disordercaused calcium oscillation rhythmic disorders in airway smooth muscle cells is closely associated with airway remodeling. It was previously found that pathological loss of PTEN promoted airway remodeling, inducing increases of intracellularcalcium and the change of calcium signal transduction molecule CD38. Based on the current situation that the uncertainty of underlying mechanism of PTEN in regulating calcium signaling, we put forward thatPTEN regulates CD38 mediated calcium oscillation in airway smooth muscle cells to affect airway remodeling during asthma. We used PTEN conditional knockout mice and mouse smooth muscle cells model, immune-cellular and molecular biological techniques, to comparatively observe the effects of PTENon calcium influx and the calcium oscillation signal within the airway smooth muscle cells and the effects on airway remodeling. Furthermore, we aims to uncover the effects and underlying mechanism of PTEN mediated inhibition of PI3K/AKT signaling pathway and the possible PTEN-CD38 interaction on the regulation of CD38 expression and activity. To further clarify PTEN-CD38-calcium oscillation-airway remodeling cascades, the inhibitors of the pathway are used to identify the underlying mechanisms in the regulation of PTEN on CD38-mediated calcium oscillation in airway remodeling. Our study will pave a promising avenue for the regulation of airway remodeling in asthma and provide a new target for the accurate treatment of asthma.