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

ncRNA afu-182 在烟曲霉唑反应和病理学中的功能作用

• 批准号: 10666674
• 负责人: Sourabh Dhingra
• 金额: $ 24.16万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666674
• 关键词: Affect; Allergic Bronchopulmonary Aspergillosis; Antifungal Agents; Aspergillus fumigatus; Azole resistance; Azoles; Biochemical; Bioinformatics; Biology; Candida albicans; Centers of Research Excellence; Clinical; Data; Development; Disease Outcome; Disease Progression; Drug Tolerance; Drug resistance; Educational workshop; Fluorescent in Situ Hybridization; Foundations; Funding; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Human; Immune; In Vitro; Infection; Itraconazole; Knowledge; Laboratories; Life; Literature; Lung infections; Measures; Mediating; Mentors; Messenger RNA; Microbe; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Modeling; Molds; Molecular; Morbidity - disease rate; Mus; Netherlands; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Predisposition; Protocols documentation; Regulator Genes; Regulatory Pathway; Regulon; Research; Research Personnel; Resistance; Role; Stress; Technology; Therapeutic; Treatment Failure; Treatment outcome; Universities; Untranslated RNA; Virulence; Voriconazole; Work; antimicrobial drug; career development; clinically relevant; design; drug development; human pathogen; improved; in vivo; innovation; insight; mortality; mouse model; nano-string; novel; pathogen; pathogenic fungus; posaconazole; posttranscriptional; prevent; resistant strain; response; single molecule; transcriptomics; treatment strategy

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.

项目概要： 由烟曲霉引起的侵袭性肺曲霉菌病 (IPA) 是发病率和死亡率的主要原因 尽管有抗真菌药物，但免疫功能低下患者的死亡率仍然很高。全球出现 唑类耐药性是导致疾病结果不佳的一个主要因素；然而，唑类耐药A. 烟曲霉分离株仅导致约 5% 的感染。知识上的一个主要差距是唑类的敏感性如何 分离株对唑类药物具有耐受性，导致疾病结果不佳，死亡率超过 50%。到 为此，我们鉴定了一种未表征的长非编码 RNA (lncRNA) afu-182，它对 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 隔离。在本提案中，我们将使用基因组学、遗传学、生化方法来定义 afu-182 介导烟曲霉的唑类药物耐受性。在具体目标 1) 中，我们将定义路径 调节唑类耐受性和 afu-182 调节子以了解唑类涉及的分子机制 宽容。在目标 2）中，我们将在小鼠模型中定义唑类应激下体内 afu-182 的表达 侵袭性肺曲霉菌病。成功完成拟议目标具有巨大潜力 通过定义唑类耐受性和解密二元相关机制来改善临床结果 真菌分离株的耐药/敏感谱。这将有助于设计更好的唑类治疗策略 易感感染以获得更好的疾病结果。