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：由曲霉菌引起的侵入性肺曲霉病（IPA）是发病率和尽管有抗真菌药物可用，但免疫受损患者的死亡率。全球出现硫唑耐药性是导致疾病不良预后的主要因素。但是，二唑耐药A。富马图斯分离株仅导致约5％的感染。知识的主要差距是唑敏敏感隔离材料可耐受氮药物，并导致疾病不良的疾病预后，死亡率超过50％。到这端，我们已经确定了一个未表征的长期非编码RNA（LNCRNA）AFU-182，否定性与硫唑药物反应相关，是实验室和临床中硫唑药物耐受性的驱动力分离物。在此提案中，我们将使用基因组学，遗传学，生化方法来定义 AFU-182在烟曲霉中介导的硫唑耐受性。在特定目标1）中，我们将定义途径调节唑的耐受性和AFU-182调节以了解偶氮的分子机制宽容。在AIM 2）中，我们将在Azole胁迫下在鼠模型中定义AFU-182体内表达侵入性肺曲霉病。成功完成拟议的目标具有巨大的潜力通过定义涉及硫磺耐受性的机制和解密二进制，改善临床结果真菌分离株的抗性/易感光谱。这将有助于设计azole的更好的治疗策略易感感染以获得更好的疾病预后。