Functional roles of ncRNA afu-182 in azole response and pathobiology of Aspergillus fumigatus

项目概要： 由烟曲霉引起的侵袭性肺曲霉病（IPA）是发病的主要原因， 免疫功能低下患者的死亡率，尽管抗真菌药物的可用性。全球范围内出现的 唑类耐药是导致疾病预后不良的主要因素;然而，唑类耐药的A. 烟曲霉分离株仅占感染的约5%。一个主要的知识缺口是如何唑敏感 分离株耐受唑类药物，导致疾病预后差，死亡率超过50%。到 为此，我们已经鉴定了一种未表征的长非编码RNA（lncRNA）afu-182， 与唑类药物反应相关，是实验室和临床中唑类药物耐受性的驱动因素 分离株在本研究中，我们将利用基因组学、遗传学、生物化学的方法来确定 afu-182介导了A.烟熏。在具体目标1）中，我们将定义路径 调节唑耐受和afu-182调节子，以了解唑的分子机制 宽容在目的2）中，我们将在唑应激的小鼠模型中定义afu-182的体内表达。 侵袭性肺曲霉病成功完成拟议目标具有巨大潜力， 通过明确唑类药物耐受机制和解密二分类来改善临床结局 真菌分离株的耐药/敏感谱。这将有助于设计更好的唑类药物治疗策略 易感感染，以实现更好的疾病结果。

Project Summary: Invasive pulmonary aspergillosis (IPA) caused by Aspergillus fumigatus is a major cause of morbidity and mortality in immune-compromised patients despite the availability of antifungal drugs. The global emergence of azole drug resistance is a major factor contributing to poor disease outcomes; however, azole drug-resistant A. fumigatus isolates contribute to only about 5% of infections. A major gap in knowledge is how azole sensitive isolates tolerate azole drugs and contribute to poor disease outcomes with mortality rates in excess of 50%. To this end, we have identified an uncharacterized long non-coding RNA (lncRNA) afu-182 that negatively correlates with azole drug response and is a driver of azole drug tolerance in the laboratory and clinical isolates. In this proposal, we will use genomics, genetics, biochemical approaches to define the mechanism of afu-182 mediated azole drug tolerance in A. fumigatus. In specific Aim 1), we will define the pathways regulating azole tolerance and afu-182 regulon to understand the molecular mechanisms involved in azole tolerance. In Aim 2), we will define the afu-182 expression in vivo under azole stress in a murine model of invasive pulmonary aspergillosis. Successful completion of proposed aims has tremendous potential to improve clinical outcomes by defining mechanisms involved in azole tolerance and declassifying binary resistant/susceptible spectrum for fungal isolates. This will help design better treatment strategies for azole susceptible infections to achieve better disease outcomes.