烟曲霉是临床重要病原真菌，可引起过敏、慢性曲霉肿以及病死率很高的侵袭性感染，其致病机制复杂，与其有效抵抗外界应激并极性生长有关。Sac1是一种磷脂酰肌醇磷酸水解酶，也是肌动蛋白相关蛋白，在哺乳动物和酵母等细胞中调控囊泡运输、分泌及信号传递等重要生理过程，但其对细胞壁完整性应激以及极性生长的影响及调控分子机制尚不清楚。我们前期发现，烟曲霉Sac1与人源的亲缘关系较远，其表达改变可显著影响细胞壁应激，而且与酵母和白念珠菌明显不同，其缺失导致烟曲霉几乎不生长。基于此，本项目拟深入研究烟曲霉Sac1及其底物在不同条件下的表达和分布变化规律，解析其对细胞壁完整性应激、多糖组成及代谢的影响及分子机制，从细胞和动物水平分析对烟曲霉致病性的影响规律。这有可能发现磷脂肌醇代谢调控真菌细胞壁完整性应激、极性生长及影响致病性的新机制，也为寻找可能的抗真菌药物靶点提供重要科学依据。

As a major pathogenic fungus, Aspergillus fumigatus is able to cause the invasive pulmonary aspergillosis with high mortality and also chronic infection and allergic disease, its pathogenic mechanism is rather complicated and unclear; however, closely associated with the resistance to stress in diverse niches and strong polarized growth. As an actin-related protein, Sac1 can hydrolyze the phosphoinositol 4-phosphate to produce the phosphoinositol and plays an important role in several physiological processes, like vesicle transportation and secretion and cell signaling in mammalian cells and yeast; however, the exact regulation mechanism of it on cell wall integrity and polarized growth is still poorly understood. Our previous study showed that with relatively distant genetic relationship with human Sac1, A. fumigatus Sac1 is indispensable for its growth and suppression of Sac1 affects obviously the sensitivity to cell wall stress. Based on these findings, we intend to characterize the expression and distribution of Sac1 and its substrate under different conditions, investigate the role of Sac1 on actin cytoskeleton rearrangement, stress response and metabolism of major polysaccharides of A. fumigatus, elucidate the molecular regulation mechanism of Sac1 on cell wall integrity signaling and analyze the effect of Sac1 on A. fumigatus pathogenicity in cells and animals. This study will demonstrate a novel regulation mechanism for cell wall stress response, cell polarized growth and pathogenicity by close relationship with phosphoinositol metabolism in filamentous fungi, which could also offer important scientific evidences for discovering some novel potential targets of antifungal drugs.