烟曲霉感染机制不明且现有抗真菌治疗效果不佳是引起侵袭性曲霉病（IA）不断增多且病死率很高的重要原因。基于发生IA时烟曲霉cAMP和calcineurin通路的重要性，尤其是我们新近关于敲除烟曲霉环化酶相关蛋白（CAP）基因可经影响calcineurin而使其应激反应增强且形态异常、生长减慢、并致烟曲霉对三唑类和棘白菌素类药物及calcineurin抑制剂高度敏感的原创性结果，我们拟：1、经基因回复、过表达及转录组测序、免疫共沉淀联合LC-MS/MS等，来揭示CAP/actin/AC、cAMP、calcineurin间的互作机制及CAP调控的靶通路/基因；2、经荧光染色和电镜观察并与宿主细胞互作的研究，以明确CAP对烟曲霉毒力及免疫致病性方面的影响；3、经动物模型，以阐明烟曲霉CAP影响IA发病和抗真菌治疗的作用。本课题对于揭示烟曲霉致病新机制、确定IA治疗新方案、发展新疗法，有重要意义。

The incidence rates and mortality of invasive aspergillosis (IA), caused by Aspergillus fumigatus, have risen dramatically since last decades. Beside the increase in the number of immunocompromised individuals, being unclear in mechanism of A. fumigatus infection and being mediocre in antifungal effect for IA have been accounted for this important problem. Calcineurin as well as cAMP-PKA pathways have been reported playing significant roles in the pathogenicity of A. fumigatus. Recently, we have shown that deletion of A. fumigatus CAP, encoding a cyclase-associated protein that can activate the cAMP-PKA pathway, leads to enhanced triazole, echinocandin and tacrolimus sensitivity, as well as morphological abnormality and decreasing growth rates. And we have also shown that deletion of A. fumigatus CAP enhances calcineurin activity. Based on these information, the followings will be performed in this proposal: 1. To reveal the pathway/gene regulated by CAP in A. fumigatus, as well as the mechanism of interaction among CAP/actin/AC, cAMP, and calcineurin, by using the strategies of gene restore and over-expression, transcriptome analyses, immune coprecipitation combined with LC-MS/MS; 2. To clarify the contribution of A. fumigatus CAP to virulence and immune-pathogenesis by observing the morphological feature of A. fumigatus with Calcoflour White staining and electron microscope, and interaction with host cell by co-culture; 3. To clarify the function of CAP in pathogenic mechanism of A. fumigatus causing IA and antifungal therapy for IA. The completion for this proposal will provide the significant basis for novel pathogenesis mechanism of A. fumigatus, therapeutic regimen and remedy for IA.