Study of the veA Gene in the Human Pathogen Aspergillus fumigatus

描述(申请人提供)：该项目的长期目标是研究可能的分子策略，通过针对真菌特有的主要调控基因来控制真菌病原体对人类健康的有害影响。在这项提案中，PI将重点关注人类病原体烟曲霉。调控信号基因在真菌物种中往往是保守的。PI的实验室小组已经证明，天鹅绒，或VEA，是一种全球调控基因，控制曲霉属物种的形态发育和次生代谢，以及镰刀菌属中的真菌属。有趣的是，VEA只在真菌中发现。烟曲霉菌是一种重要的人类病原体，对免疫抑制者具有很高的死亡率。VEA基因的缺失影响了不同的细胞过程，这一事实表明VEA也可能是烟曲霉多因素致病的关键因素。PI打算通过研究VEA依赖的化合物，特别是次生代谢产物，来探索VEA在烟曲霉菌中的作用，这些化合物可能与真菌疾病有关。在这项建议中，VEA突变株的毒力也将在小鼠感染模型中直接进行评估。这些基础研究将为VEA靶向控制人类病原体的潜力提供必要的基础。 公共卫生相关性：VEA是真菌特有的全球调控基因，控制曲霉和其他真菌属的发育和次生代谢。我们将通过研究VEA依赖的化合物，如可能导致疾病的次生代谢物，来探索VEA在致病烟曲霉菌中的作用。VEA在毒力中的作用也将通过小鼠感染来直接评估。

DESCRIPTION (provided by applicant): The long term goal of this project is to investigate possible molecular strategies to control the detrimental effects of fungal pathogens on human health by targeting major regulatory genes that are unique to fungi. In this proposal the PI will focus on the human pathogen, Aspergillus fumigatus. Regulatory signaling genes tend to be conserved among fungal species. The PI's laboratory group has demonstrated that velvet, or veA, is a global regulatory gene that controls both morphological development and secondary metabolism in species of the genus Aspergillus, and across fungal genera in Fusarium spp. Interestingly, VeA has only been found in fungi. Aspergillus fumigatus has emerged as an important human pathogen with high mortality rates for the inmmunosuppressed. The fact that deletion of veA affects different cellular processes suggests that veA could also be a key factor in A. fumigatus multifactorial pathogenesis. The PI intends to explore the role veA in A. fumigatus by study veA-dependent compounds, particularly secondary metabolites, which may contribute to fungal disease. In this proposal, virulence of the veA mutant strains will also be directly assessed in a murine infection model. These basic studies will provide an essential foundation into the potential of VeA- targeting to control human pathogens. PUBLIC HEALTH RELEVANCE: veA is a global regulatory gene unique to fungi that controls development and secondary metabolism in Aspergillus and other fungal genera. We will explore the role veA in the pathogenic A. fumigatus by studying veA-dependent compounds, such as secondary metabolites that may contribute to disease. The role of veA in virulence will also be directly assessed through murine infection.