新生隐球菌是一种重要人类病原真菌。其细胞壁组分在免疫识别及药物耐受等方面扮演了重要的角色。N-乙酰葡萄糖胺（GlcNAc）的代谢与关键细胞壁组分几丁质和壳聚糖的形成高度关联。然而，其胞内代谢与调控的分子基础以及对该菌的毒力表征的贡献尚不清楚。申请人前期研究鉴定了新生隐球菌完整的GlcNAc分解代谢基因簇，发现该菌利用一个新颖的N-乙酰葡萄糖胺激酶（Hxk1）和未报道的核心调控因子Gcr1参与GlcNAc的代谢及调控，并揭示GlcNAc代谢稳态与高毒泰坦细胞的产生高度相关。本项目拟利用遗传学，细胞生物学和生物化学手段，以GlcNAc代谢的核心酶Hxk1催化反应的分子基础，及关键转录因子Gcr1调控机制为研究重心，对新生隐球菌GlcNAc分解代谢调控的核心步骤进行探索，并进而解析GlcNAc分解代谢与形成泰坦细胞之间的分子关联。本项目研究结果将为寻找控制新生隐球菌感染的新途径奠定基础。

Crptocococcus neoformans is an important human pathogen, in which the cell wall components play an essential role in immune reorganization and drug tolerance. Metabolism of N-acetylglucosamine (GlcNAc) is highly connected with the two key components of cell wall, such as chitin and chitosan. However, the molecular mechanism of its catabolic metabolism and its function in pathogenesis remained unsolved. In the preliminary experiment, we identified the whole GlcNAc catabolic gene cluster in C. neoformans and found a novel acetylglucosamine kinase(Hxk1) and a key transcription factor Gcr1. Importantly, we found that GlcNAc induced the production of the titan cell, the unique and important morphotype involved in pathogenesis and drug resistance. In this proposal, we integrate genetics, molecular biology and biochemistry technique to elucidate the underlying mechanism of Hxk1, which generate the key intermediate of GlcNAc pathway, to reveal the regulation mechanism of Gcr1 controlling the gene expression of the GlcNAc cluster, and to build the molecular connection between GlcNAc metabolism and production of titan cell. The results will not only be important for understanding mechanism of pathogenesis, but also lay down a great foundation in the development of new strategies to control infections caused by C. neoformans