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Investigating the function of macrophages in the efficacy of anti-fungal drugs in larval zebrafish

研究巨噬细胞在斑马鱼幼体抗真菌药物疗效中的功能

基本信息

批准号：
10494468
负责人：
Emily Rosowski
金额：
$ 25.01万
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/10494468
关键词：
AIDS/HIV problem Adjuvant Therapy Adrenal Cortex Hormones Affect Animals Antifungal Agents Aspergillus fumigatus Automobile Driving Azoles Bioinformatics Biological CRISPR/Cas technology Candidate Disease Gene Cell Culture Techniques Cells Centers of Research Excellence Clinic Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Development Disease Drug Synergism Drug usage Environment Future Gene Expression Gene Transfer Techniques Generations Genes Genetic Genetic Transcription Genomics Goals Growth Hematopoietic Stem Cell Transplantation Human Image Immune Immune response Immune system Immunocompetent Immunocompromised Host Immunotherapeutic agent Immunotherapy In Vitro Individual Infection Inflammatory Itraconazole Larva Life Light Mediating Methods Modeling Mutagenesis Mutate Mycoses Organ Transplantation Organism Oxidases Pathogenesis Pathway interactions Patients Pattern recognition receptor Persons Phagocytes Phagocytosis Pharmaceutical Preparations Pharmacotherapy Positioning Attribute Process Reactive Oxygen Species Receptor Signaling Research Resources Risk Signal Transduction Survival Rate System Testing Universities Voriconazole Work Zebrafish bafilomycin A base drug discovery drug efficacy drug testing efficacy testing experimental study fighting fungus imaging facilities imaging genetics immunosuppressed in vivo innovation macrophage microbial mutant overexpression pathogen pathogenic fungus posaconazole prevent receptor synergism tissue culture tool transcriptome sequencing uptake

项目摘要

Project Summary/Abstract Fungal pathogens cause life-threatening disease in immuno-compromised patients, with more than 2 million people affected world-wide each year. Anti-fungal drugs that are used in the clinic to treat patients are ineffective, even though these drugs work well against fungi in a petri dish. The overarching goal of the proposed research is to increase the efficacy of these drugs inside of living organisms. The larval zebrafish is an ideal host in which to tackle this problem. Excellent live imaging and genetic tools are available, the immune systems of zebrafish and humans are largely conserved, and fungal infection models in zebrafish recapitulate pathogenesis in humans. Preliminary data indicates that synergy between the anti-fungal drug voriconazole and macrophages in vivo increases killing of the fungal pathogen Aspergillus fumigatus. I propose to identify genes and pathways in macrophages that are modulated by azole treatment and that promote azole-mediated fungal killing. First, I will focus on known cell biological pathways involved in pathogen recognition and phagosomal killing, including pathogen recognition receptor (PRR) pathways, reactive oxygen species (ROS) generation, and phagosomal acidification. Then, I will use an unbiased RNAseq-based approach to identify unknown genes that are modulated by azole treatment. Hits from both of these approaches could be targeted in the future for adjuvant therapy to boost anti-fungal efficacy in infected hosts. Altogether, results from this proposal will identify new targets for immuno- therapeutic adjuvant therapy to increase the efficacy of anti-fungal treatment in patients.

项目总结/摘要真菌病原体在免疫功能低下的患者中引起危及生命的疾病，全世界每年有100万人受到影响。临床上用于治疗的抗真菌药物病人是无效的，即使这些药物对培养皿中的真菌效果很好。的拟议研究的总体目标是提高这些药物在体内的疗效。活的有机体斑马鱼幼鱼是解决这一问题的理想宿主。优秀的现场虽然有成像和遗传工具，但斑马鱼和人类的免疫系统在很大程度上斑马鱼中保守的和真菌感染模型再现了人类的发病机制。初步数据表明，抗真菌药物伏立康唑和体内巨噬细胞之间的协同作用增加对真菌病原体烟曲霉的杀灭。我建议识别基因，巨噬细胞中受唑处理调节并促进唑介导真菌杀灭首先，我将集中在已知的细胞生物学途径参与病原体识别和吞噬体杀伤，包括病原体识别受体（PRR）途径，活性氧物种（ROS）的产生和吞噬体酸化。然后，我将使用一个基于无偏RNAseq的方法来确定未知的基因是由唑治疗调制。这两个都有这些方法在未来可以作为辅助治疗的目标，以提高抗真菌治疗的疗效。感染的宿主总之，这项提议的结果将确定免疫治疗的新靶点，治疗性辅助治疗，以提高患者抗真菌治疗的疗效。