Investigating the function of macrophages in the efficacy of anti-fungal drugs in larval zebrafish
Investigating the function of macrophages in the efficacy of anti-fungal drugs in larval zebrafish
批准号:
10494468
负责人:
Emily Rosowski
金额:
$25.01万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-15 至 2027-05-31
关键词:
AIDS/HIV problemAdjuvant TherapyAdrenal Cortex HormonesAffectAnimalsAntifungal AgentsAspergillus fumigatusAutomobile DrivingAzolesBioinformaticsBiologicalCRISPR/Cas technologyCandidate Disease GeneCell Culture TechniquesCellsCenters of Research ExcellenceClinicClustered Regularly Interspaced Short Palindromic RepeatsComplexDataDevelopmentDiseaseDrug SynergismDrug usageEnvironmentFutureGene ExpressionGene Transfer TechniquesGenerationsGenesGeneticGenetic TranscriptionGenomicsGoalsGrowthHematopoietic Stem Cell TransplantationHumanImageImmuneImmune responseImmune systemImmunocompetentImmunocompromised HostImmunotherapeutic agentImmunotherapyIn VitroIndividualInfectionInflammatoryItraconazoleLarvaLifeLightMediatingMethodsModelingMutagenesisMutateMycosesOrgan TransplantationOrganismOxidasesPathogenesisPathway interactionsPatientsPattern recognition receptorPersonsPhagocytesPhagocytosisPharmaceutical PreparationsPharmacotherapyPositioning AttributeProcessReactive Oxygen SpeciesReceptor SignalingResearchResourcesRiskSignal TransductionSurvival RateSystemTestingUniversitiesVoriconazoleWorkZebrafishbafilomycin Abasedrug discoverydrug efficacydrug testingefficacy testingexperimental studyfightingfungusimaging facilitiesimaging geneticsimmunosuppressedin vivoinnovationmacrophagemicrobialmutantoverexpressionpathogenpathogenic fungusposaconazolepreventreceptorsynergismtissue culturetooltranscriptome sequencinguptake
中文摘要
项目摘要/摘要
在免疫功能低下的患者中,真菌病原体会导致危及生命的疾病,有超过2种
全球每年有数百万人受到影响。临床上用于治疗的抗真菌药物
患者是无效的,即使这些药物对培养皿中的真菌很有效。这个
这项拟议研究的首要目标是提高这些药物在
活着的有机体。斑马鱼幼体是解决这一问题的理想宿主。精彩的现场直播
成像和遗传工具是可用的,斑马鱼和人类的免疫系统在很大程度上
斑马鱼中的保守和真菌感染模型概括了人类的发病机制。初步
数据表明,抗真菌药物伏立康唑与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作用。我建议识别基因和
巨噬细胞中受唑处理调节并促进唑介化的通路
真菌致死。首先,我将重点介绍病原体识别所涉及的已知细胞生物学途径。
和吞噬体杀,包括病原体识别受体(PRR)途径,活性氧
物种(ROS)的生成和吞噬体酸化。然后,我将使用基于RNAseq的无偏见
一种识别受唑类药物调控的未知基因的方法。这两个网站的点击率都是
未来可能有针对性的辅助治疗方法,以提高抗真菌疗效
受感染的宿主。总之,这项提案的结果将确定免疫的新靶点。
治疗辅助治疗,提高患者抗真菌治疗的疗效。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Developing an in vivo toolbox to interrogate the intracellular trafficking and killing of Aspergillus spores
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批准号:10569606
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项目类别:
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资助金额:$18.62万
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财政年份:2022
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负责人:Emily Rosowski
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依托单位:
Deciphering macrophage versus neutrophil signaling and effector functions in immune responses in vivo
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批准号:10501204
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项目类别:
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资助金额:$33.55万
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财政年份:2022
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负责人:Emily Rosowski
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依托单位:
Deciphering macrophage versus neutrophil signaling and effector functions in immune responses in vivo
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批准号:10798449
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项目类别:
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资助金额:$3.18万
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财政年份:2022
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负责人:Emily Rosowski
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依托单位:
Developing an in vivo toolbox to interrogate the intracellular trafficking and killing of Aspergillus spores
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批准号:10453136
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项目类别:
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资助金额:$22.45万
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财政年份:2022
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负责人:Emily Rosowski
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依托单位:
Deciphering macrophage versus neutrophil signaling and effector functions in immune responses in vivo
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批准号:10661094
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项目类别:
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资助金额:$33.55万
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财政年份:2022
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负责人:Emily Rosowski
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依托单位:
The Role of Rac and ROS in the Control of Aspergillus Infection
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批准号:8777692
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项目类别:
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资助金额:$4.99万
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财政年份:2014
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负责人:Emily Rosowski
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依托单位:
The Role of Rac and ROS in the Control of Aspergillus Infection
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批准号:8927333
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项目类别:
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资助金额:$5.24万
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财政年份:2014
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负责人:Emily Rosowski
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依托单位:
海外基金