Regulation of Intrinsic Caspofungin Resistance in C. neoformans
新型隐球菌内在卡泊芬净耐药性的调节
基本信息
- 批准号:9761969
- 负责人:
- 金额:$ 22.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-08 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos Untranslated RegionsAcquired Immunodeficiency SyndromeAmino Acid SequenceAmphotericin BAntifungal AgentsAntifungal TherapyArginineBindingC-terminalCaspofunginCell WallCellsCellular ImmunityCessation of lifeConsensusCryptococcosisCryptococcusCryptococcus neoformansCryptococcus neoformans infectionDataDefectDrug TargetingElementsExhibitsFluconazoleFlucytosineFoundationsFungal ProteinsFutureGeneticGenetic TranscriptionHypersensitivityImmunocompromised HostIn VitroIndustrial fungicideLeadLinkMeningitisMessenger RNAMethylationModelingMutagenesisMutationPathogenicityPatientsPharmaceutical PreparationsPolyadenylationPost-Transcriptional RegulationPredispositionProtein-Arginine N-MethyltransferaseProteinsRNA BindingRNA Recognition MotifRNA-Binding ProteinsRegulationResistanceResourcesRibosomesRoleSiteTestingTranslatingTranslationsTransplant RecipientsWorkechinocandin resistanceglucan synthasein vivoinhibitor/antagonistmRNA Stabilitymortalitymutantprotein Bresistance mechanismstressor
项目摘要
Abstract:
Cryptococcosis causes hundreds of thousands of deaths per year, mostly in resource-poor settings. C.
neoformans exhibits intrinsic resistance to echinocandin antifungals, eliminating this safe and effective class of
antifungal drug from the anti-cryptococcal arsenal. The mechanism of resistance is unknown, but it is
independent of drug target inhibition, as the target protein, the β-1,3-glucan synthase Fks1, is sensitive to the
drug. We have identified a regulator of caspofungin sensitivity in C. neoformans, Puf4, that controls the FKS1
mRNA at the level of stability, and a puf4 mutant is caspofungin resistant. Deletion putative post-translational
regulator of Puf4, the protein arginine methyltransferase (PRMT) Rmt5, confers hypersensitivity to
caspofungin, suggesting a role for arginine methylation in the regulation of Puf4 function and caspofungin
sensitivity. Our scientific premise is that Puf4 controls caspofungin sensitivity through post-transcriptional
regulation of the FKS1 mRNA, and that the ability of Puf4 to regulate FKS1 is dependent on its methylation
status. We will investigate the mechanism of Puf4 regulation including its binding to the FKS1 mRNA 5’ UTR
and the effect of that interaction on translation and mRNA stability (Aim 1). We will then investigate the role of
Puf4 methylation on its ability to regulate the FKS1 mRNA including the effect of rmt5 deletion on FKS1 post-
transcriptional regulation, the identification of methylation sites on Puf4 and the use of mutagenesis to
determine the consequence of methylation on effector function (Aim 2). PRMTs are known drug targets.
Determining the mechanism by which Rmt5 and its putative target Puf4 control caspofungin sensitivity may
lead to adjunctive therapies to potentiate the anti-cryptococcal activity of echinocandins.
摘要:
隐球菌病每年造成数十万人死亡,大多数发生在资源贫乏的环境中。C.
新变形杆菌对棘白菌素类抗真菌药物表现出内在耐药性,消除了这类安全有效的
抗隐球菌的抗真菌药耐药机制尚不清楚,但它是
与药物靶点抑制无关,因为靶蛋白β-1,3-葡聚糖合酶Fks 1对药物靶点抑制敏感。
药我们已经确定了卡泊芬净敏感性的调节因子。控制FKS 1的新型人Puf 4
mRNA水平的稳定性,并且puf 4突变体是卡泊芬净耐药的。推定翻译后缺失
Puf 4的调节剂,蛋白质精氨酸甲基转移酶(PRMT)Rmt 5,赋予对
这表明精氨酸甲基化在调节Puf 4功能和卡泊芬净中的作用。
灵敏度我们的科学前提是Puf 4通过转录后调节卡泊芬净的敏感性。
Puf 4调控FKS 1 mRNA的能力依赖于其甲基化
status.我们将研究Puf 4的调控机制,包括其与FKS 1 mRNA 5' UTR的结合,
以及这种相互作用对翻译和mRNA稳定性的影响(目的1)。然后我们将研究
puf 4甲基化对其调控FKS 1 mRNA能力的影响,包括rmt 5 β缺失对FKS 1表达后的影响。
转录调控,Puf 4上甲基化位点的鉴定和诱变的使用,
确定甲基化对效应子功能的影响(目的2)。PRMT是已知的药物靶标。
确定Rmt 5及其假定靶点Puf 4控制卡泊芬净敏感性的机制可能
导致增强棘白菌素抗隐球菌活性的连续疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John C Panepinto其他文献
John C Panepinto的其他文献
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{{ truncateString('John C Panepinto', 18)}}的其他基金
Ribosome Heterogeneity in Cryptococcus neoformans
新型隐球菌的核糖体异质性
- 批准号:
10687190 - 财政年份:2021
- 资助金额:
$ 22.56万 - 项目类别:
Ribosome Heterogeneity in Cryptococcus neoformans
新型隐球菌的核糖体异质性
- 批准号:
10391779 - 财政年份:2021
- 资助金额:
$ 22.56万 - 项目类别:
Ribosome Heterogeneity in Cryptococcus neoformans
新型隐球菌的核糖体异质性
- 批准号:
10494146 - 财政年份:2021
- 资助金额:
$ 22.56万 - 项目类别:
Stress Responsive Reprogramming of Translating mRNA Pools in C. neoformans
新型隐球菌中翻译 mRNA 库的应激反应性重编程
- 批准号:
9913456 - 财政年份:2017
- 资助金额:
$ 22.56万 - 项目类别:
Stress Responsive Reprogramming of Translating mRNA Pools in C. neoformans
新型隐球菌中翻译 mRNA 库的应激反应性重编程
- 批准号:
10088140 - 财政年份:2017
- 资助金额:
$ 22.56万 - 项目类别:
Stress-Responsive RNA Regulons in Cryptococcus neoformans
新型隐球菌中的应激反应性 RNA 调节子
- 批准号:
8050342 - 财政年份:2011
- 资助金额:
$ 22.56万 - 项目类别:
Stress-Responsive RNA Regulons in Cryptococcus neoformans
新型隐球菌中的应激反应性 RNA 调节子
- 批准号:
8487347 - 财政年份:2011
- 资助金额:
$ 22.56万 - 项目类别:
Stress-Responsive RNA Regulons in Cryptococcus neoformans
新型隐球菌中的应激反应性 RNA 调节子
- 批准号:
8293351 - 财政年份:2011
- 资助金额:
$ 22.56万 - 项目类别:
Stress-Responsive RNA Regulons in Cryptococcus neoformans
新型隐球菌中的应激反应性 RNA 调节子
- 批准号:
8676642 - 财政年份:2011
- 资助金额:
$ 22.56万 - 项目类别:
Ccr4 in the maintenance of thermotolerance and pathogenicity of C. neoformans
Ccr4 在维持新型隐球菌的耐热性和致病性中的作用
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7261535 - 财政年份:2008
- 资助金额:
$ 22.56万 - 项目类别:
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