白念珠菌肌醇多磷酸代谢途径调控细胞自噬的分子机制研究

白假丝酵母是人类重要的条件致病真菌，揭示其耐受环境压力的分子机制是病原真菌领域的研究热点。自噬作为白假丝酵母胞内成分更新的关键策略，其精细调控对该菌的细胞存活及压力耐受至关重要，申请人前期发现肌醇多磷酸代谢途径参与细胞自噬过程，但该调控的分子机制尚未明确。本项目以白假丝酵母肌醇多磷酸代谢途径为研究对象，系统鉴定肌醇多磷酸代谢相关蛋白成员，采用代谢组学与表型分析方法确证其在催化肌醇多磷酸代谢及自噬调控过程中的功能；在发掘该菌TORC1依赖性自噬调控因子的基础上，采用免疫共沉、荧光标记共定位、硫藤黄菌素阻断及RT-PCR等技术，探究肌醇多磷酸代谢途径对TORC1依赖性调控因子、钙依赖性自噬及非TORC1依赖性自噬的调控作用，阐明该途径调控白假丝酵母自噬的分子机制。相关研究成果有望揭示肌醇多磷酸代谢途径与细胞自噬的相互关系，丰富对真菌自噬调控网络的认识，为临床治疗病原真菌感染提供新的药物靶点。

Candida albicans is one of the most serious opportunistic fungal pathogens in clinic. It is a hot topic to uncover the molecular mechanisms by which the fungus tolerates environmental stress. Autophagy is the key strategy of renewing intracellular components by this fungus, and hence accurate regulation of autophagy is critical for its survival and stress tolerance. The applicant previously discovered the inositol polyphosphate metabolism pathway involving in the process of autophagy, but whose molecular mechanisms remain unknown. This study aims to systematically identify the members of inositol polyphosphate metabolism, and verify their role in this metabolism pathway and regulation of autophagy. Based on uncovering the TORC1-dependent autophagy regulation factors, this study further investigates the function of inositol polyphosphate metabolism pathway in regulating TORC1-dependent factors, calcium-dependent autophagy, and TORC1-independent autophagy, elucidating the molecular mechanisms by which the inositol polyphosphate metabolism pathway regulates autophagy. The achievements will shed a novel light on the relationship between inositol polyphosphate metabolism and autophagy, bring novel knowledge in autophagy regulation network, and provide new molecular targets during clinically antifungal treatments.