Caspace Activity and Virulence of Aspergillus Fumigatus

描述（由申请方提供）：机会性霉菌病原体烟曲霉的感染持续增加，主要是由于器官移植的增加和使用更积极的免疫抑制方案。尽管抗真菌治疗取得了一些进展，侵袭性曲霉病的预后仍然很差，死亡率接近90%，强调需要新的和更有效的治疗靶点。 半胱天冬酶依赖的程序性细胞死亡（PCD）是高等真核生物中高度保守的应激反应，并且细胞凋亡信号机制的组分被认为是最有希望的抗癌靶点之一。最近的研究表明，芽殖酵母具有一种不同的半胱天冬酶，在细胞程序死亡中发挥作用，这表明真菌半胱天冬酶也可能代表潜在的治疗靶点。caspase活性对A.烟曲霉是未知的。我们的初步数据表明，半胱天冬酶活性诱导A。烟曲霉中caspase基因的缺失突变体，以及烟曲霉中caspase基因的缺失突变体。烟曲霉基因组对氧化应激具有抗性。本研究的目的是确定这些半胱天冬酶对A.烟熏。利用A.我们建议测试以下假设： 1.该半胱天冬酶活性是最佳菌丝生长所需的，特别是在体内会遇到的应激条件下。 2.在播散性侵袭性曲霉病小鼠模型中，半胱天冬酶活性是野生型毒力表达所必需的。

DESCRIPTION (provided by the applicant): Infections with the opportunistic mould pathogen Aspergillus fumigatus are continuing to increase, primarily as a consequence of the rise in organ transplantation and the use of more aggressive immunosuppressive regimens. Despite some advances in antifungal therapy the prognosis for invasive aspergillosis remains poor, with mortality rates approaching 90%, emphasizing the need for new and more effective therapeutic targets for this organism. Caspase-dependent programmed cell death (PCD) is a highly conserved stress response in higher eukaryotes, and components of the apoptosis signaling machinery are considered to be among the most promising anti-cancer targets. Recent studies have shown that budding yeast have a divergent caspase that has a role in PCD, suggesting that fungal caspases may also represent potential therapeutic targets. However, the contribution of caspase activity to growth and virulence of A. fumigatus is unknown. Our preliminary data indicate that caspase activity is induced in A. fumigatus by environmental stress, and that a mutant lacking both of the caspase genes in the A. fumigatus genome is resistant to oxidative stress. The aim of this proposal is to determine the contribution of these caspase to the growth and virulence of A. fumigatus. Using mutants of A. fumigatus with deregulated caspase activity we propose to test the following hypotheses: 1. That caspase activity is required for optimal mycelial growth, particularly under conditions of stress that would be encountered in vivo. 2. That caspase activity is required for the expression of wild type virulence in a mouse model of disseminated invasive aspergillosis.