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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.

项目摘要：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抗性/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。