白色念珠菌经MFS转运蛋白与细胞交互应答重塑口腔黏膜病微环境代谢的作用机制研究

真菌感染是口腔黏膜病发生发展的重要因素，其外排代谢产物重塑黏膜细胞外微环境致细胞能量代谢失衡，产生的不良代谢产物又与真菌交互促进，形成恶性循环。前期已建立高表达MFS转运蛋白的独特酿酒酵母系统；证实白念菌外排代谢产物含乙醛及脂肪酸；且与其共培养的黏膜细胞线粒体自噬下调，ROS堆积。推测：口腔白念菌经MFS转运蛋白外排脂肪酸及乙醛，乙醛修饰黏膜细胞线粒体融合/裂解关键蛋白、自噬相关蛋白及氧化磷酸化关键酶，改变线粒体网络形态，引起线粒体自噬不足、产能异常，ROS及乳酸堆积、外排。胞外酸化及过氧化环境又促进白念菌生长、其外排脂肪酸转化为活性醛，细胞与白念菌交互重塑微环境，致口腔黏膜念珠菌病甚至上皮异常增生。基于该假设，项目组以代谢组学为切入点，分析白念菌对细胞代谢微环境的影响，并以MFS酿酒酵母系统精准研究其作用靶点，从全新角度诠释口腔黏膜念珠菌病的病生过程，为研究其发病机制及治疗提供新思路。

Fungal infection is an important virulent factor in the development of oral mucosal lesions. By remodeling the extracellular microenvironment of the mucosa, microbial efflux metabolites disrupt the balance of host cell energy metabolism as well as promote fungal growth, forming a vicious cycle. In our study, an efficient MFS expression via S. cerevisiae cell model has been established. We have also proved that acetaldehyde and fatty acids were secreted by C. albicans, and mitochondrial autophagy and ROS were downregulated and accumulated respectively in the oral mucosal cells-C. albicans coculture. Therefore, we proposed that oral albacore secrets fatty acids and acetaldehyde through MFS transporters. Acetaldehyde modifies key proteins of mitochondrial fusion and lysis, autophagy-related proteins, and key enzymes involve in oxidative phosphorylation to change the mitochondrial functional network. These lead to insufficient mitochondrial autophagy, abnormal productivity, accumulation, and efflux of ROS and lactic acid. Extracellular acidification and peroxide microenvironment also promote the growth of C. albicans and secretion of fatty acids, which in term metabolize into active aldehydes and modify the oral microenvironment. Ultimately, lead to oral mucosal candidiasis and epithelial dysplasia. Based on the hypothesis, the project team will take metabolic as the starting point to analyze the effects of C. albicans on the cellular metabolic microenvironment, and accurately studied its targets with MFS brewing yeast system.The project will elucidate the pathogenesis of oral mucosal candidiasis from a new perspective, providing novel ideas for studying oral fungal pathogenesis and treatments.