铁是生物体必需元素之一。由于人体内铁元素多以微生物不能直接利用的铁蛋白形式存在，所以微生物能够从宿主体内成功获取铁是其成为病原菌的关键。另一方面，胞内铁过量会对细胞产生毒害作用。因此，病原菌会进化出一套严格的铁平衡调控机制来维持其在宿主体内的生长。研究表明，病原菌中参与铁平衡的关键调节基因同时也与其致病力密切相关。然而，目前对铁平衡调控机制的认识还非常有限。本项目以引起侵袭性曲霉病的主要病原菌烟曲霉为材料，通过对T-DNA随机插入突变体库的筛选，获得了一个烟曲霉中铁平衡的关键调控因子IhrA。进一步的工作将围绕铁平衡的分子调控机理这一主题，研究IhrA在烟曲霉中对铁吸收和利用的功能，筛选和鉴定IhrA直接调控的铁平衡相关基因和与IhrA协同作用的蛋白，阐明IhrA在烟曲霉中铁平衡的分子调控机理。本项目的开展将会加深我们对病原菌铁平衡调控机制的认识，为防治曲霉感染提供新的思路。

Iron is an essential element for most organisms, as it is a cofactor in key metabolic processes such as nucleotide biosynthesis or energy production. Although iron is the second most abundant metal on earth, its bioavailability is very low in an aerobic environment because iron is mostly present as insoluble ferric hydroxides. This task is particularly challenging for pathogenic microorganisms, since iron is tightly bound to host proteins such as transferrin or lactoferrin to maintain homeostasis and to restrict access by pathogens through by innate nutritional defense. Therefore, iron acquisition during infection of a human host is a challenge that must be surmounted by every successful pathogenic microorganisms. On the other hand, an excess of iron within cells can be deleterious on account of catalysis of cell-damaging reactive oxygen species (ROS) via Haber Weiss/Fenton reactions. Therefore, all organisms especially the pathogenic microorganisms have developed highly regulated strategies to regulate the iron homeostasis. It has been reported that the key regulators of iron homeostasis in pathogenic microorganisms also played important roles in virulence. However, our knowledge of the molecular regulation mechanisms of the iron homeostasis in pathogenic microorganisms is rather limited. Aspergillus fumigatus is the most common cause of airborne fungal infections worldwide. The most serious disease caused by A. fumigatus is invasive aspergillosis (IA) when susceptible individuals in especial immunosuppressed patients inhale conidia. To identify the iron homeostasis related genes in A. fumigatus, a random mutagenesis library constructed by Agrobacterium tumefaciens-mediated transformation (ATMT) was screened. The resulting mutant showed serious growth defects under iron-depleted conditions while almost identical phenotypes with wild type stain in iron-replete conditions. The target gene was then cloned by thermal asymmetric interlaced PCR and the bioinformatics analysis showed that it encoded a predicted Zn(2)Cys(6) DNA-binding protein with function uncharacterized in fungi. Due to its function in A. fumigatus iron homeostasis, the protein is referred to as IhrA (Iron Homeostasis Regulator A). The study will focus on the roles of IhrA on the iron homeostasis in A.fumigatus through analyzing the genetic functions of IhrA in the iron uptake and utilization, studying the regulation relationships between IhrA and the conserved transcription factors in fungal iron homeostasis, HapX and SreA. We will further screen and confirm the key candidate genes downstream of IhrA and the interaction proteins which formed complexes with IhrA in the regulation of iron homeostasis in A. fumigatus. Those results will deepen our understanding on the iron homeostasis regulatory mechanisms in pathogenic fungi and provide the theory bases to control the aspergillosis.