MEF2D及其能量代谢-免疫双重调节在大气细颗粒物致气道上皮屏障损伤修复中的机制研究

Previous studies on particulate matter induced airway diseases have mainly focused on airway inflammation as the primary pathogenesis. Airway repair after exposure to particulate matter have yet to be clarified. Our previous study detected the expression of MEF2D in bronchial epithelia and its corresponding effect on energy metabolism and airway inflammation, leading to the hypothesis of a plausible metabolic-immune dual effect of MEF2D in the pathogenesis of airway diseases after exposure to particulate matter. In airway epithelial cells, MEF2D may play as a metabolic-immune dual factor with distinct physiological activities. After exposure to particulate matter, dephosphorylated MEF2D can down-regulate epithelial metabolic activity as well as up-regulate airway inflammation. To identify this assumption, we attempt to isolate and culture bronchial epithelial cells from mice models to examine the key function of MEF2D through in vivo experiments. Furthermore, we propose to establish Flag-MEF2D-16HBE stable cell strains and identify the downstream target genes through in vitro experiments. This study will allow us to explore the potential mechanisms of MEF2D in airway diseases in individuals exposed to particulate matter, providing new insights on the pathogenesis and new strategies for drug research.

大气细颗粒物影响气道上皮屏障损伤后修复的机制尚不明确。我们前期研究发现MEF2D表达于气道上皮细胞，其能量代谢-免疫双重调节作用可能影响气道上皮修复。本课题提出MEF2D介导的能量代谢-免疫双重调节机制参与大气细颗粒物致气道损伤后修复过程的假说。我们假设在气道上皮细胞接触大气细颗粒物后，一方面MEF2D去磷酸化后负性调控上皮细胞的能量合成代谢；另一方面作为转录因子上调气道炎症，而通过调控MEF2D去磷酸化过程，可以促进气道损伤后的修复过程。为验证这个假说，本课题拟构建大气细颗粒物诱导小鼠气道损伤模型，阐明MEF2D去磷酸化水平与能量代谢、免疫炎症的关系；拟构建MEF2D稳转细胞株，采用染色质免疫共沉淀结合测序技术等手段，探究MEF2D下游靶基因。本课题拟从分子、细胞和整体水平阐述MEF2D及其能量代谢-免疫双重调节作用在大气细颗粒物致气道上皮损伤修复中的机制，探索潜在治疗靶点。

气道上皮屏障损伤后修复的机制尚不明确。我们前期研究发现MEF2D表达于气道上皮细胞，其能量代谢-免疫双重调节作用可能影响气道上皮修复。本课题阐明MEF2D介导的能量代谢-免疫双重调节机制参与气道损伤后修复过程。我们证实在气道上皮细胞损伤修复过程中，一方面MEF2D负性调控上皮细胞的能量合成代谢；另一方面作为转录因子上调气道炎症，而通过调控MEF2D可以促进气道损伤后的修复过程。本课题构建小鼠气道损伤模型，阐明MEF2D与能量代谢、免疫炎症的关系；采用体内单细胞测序测序技术等手段，探究气道损伤后上皮细胞能量代谢-免疫炎症相关基因改变以及其MEF2D下游靶基因。本课题从分子、细胞和整体水平解释MEF2D及其能量代谢-免疫双重调节作用在气道上皮损伤修复中的机制，探索潜在治疗靶点。