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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

基本信息

批准号：
10494467
负责人：
Sourabh Dhingra
金额：
$ 24.78万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10494467
关键词：
Address 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 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 prevent resistant strain response single molecule transcriptomics treatment strategy

项目摘要

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.

项目总结：由烟曲霉菌引起的侵袭性肺曲霉病(IPA)是一种主要的发病率和致病因素。尽管有抗真菌药物，但免疫受损患者的死亡率。全球范围内出现的唑类耐药是导致疾病转归较差的主要因素；烟熏菌分离株仅占感染的5%左右。知识上的一个主要差距是对唑类的敏感程度分离株耐受唑类药物，导致死亡率超过50%的疾病结局不佳。至为此，我们已经鉴定出一种未鉴定的长非编码RNA(LncRNA)Afu-182，它具有负性与唑类药物反应相关，并在实验室和临床上是唑类药物耐受性的驱动因素分离株。在这个提案中，我们将使用基因组学、遗传学、生化方法来定义 AFU-182介导唑类药物在烟曲霉菌中的耐药在具体目标1)中，我们将定义路径调节唑耐受性和AFU-182调节子以了解唑类药物的分子机制宽容。在目的2)，我们将确定在活体内的AFU-182的表达，在唑类应激下，在一个小鼠模型侵袭性肺曲霉菌病。成功完成拟议的目标具有巨大的潜力通过确定与唑类耐药有关的机制和解密二元组来改善临床结果真菌分离株的抗性/敏感谱。这将有助于设计更好的唑类治疗策略。易受感染，以实现更好的疾病结果。