Regulation of Candida albicans gene expression in response to host environmental stresses
白色念珠菌基因表达响应宿主环境胁迫的调节
基本信息
- 批准号:10867738
- 负责人:
- 金额:$ 58.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos Untranslated RegionsAcquired Immunodeficiency SyndromeAddressAffectAntibioticsAntifungal AgentsBindingBinding ProteinsBioinformaticsBiological AssayCancer PatientCandida albicansCandidiasisCell WallCell membraneComplexCryptococcus neoformansDefectDevelopmentDisseminated candidiasisEIF-2alphaEnvironmentEpitopesEukaryotic Initiation Factor-4FFungal Drug ResistanceGene ExpressionGenesGenetic TranscriptionGoalsGrowthHIV/AIDSHospitalsHumanImmuneImmunocompromised HostIndividualInfectionLinkMacrophageMediatingMembraneMessenger RNAMorphologyMucous MembraneMutationOrthologous GeneOsmosisOxidative StressPathogenesisPathogenicityPatientsPhagocytesPhosphorylationPhosphotransferasesPlayPredispositionProcessProteinsPublic HealthRegulationRibosomesRoleSaccharomyces cerevisiaeSepsisSignal PathwayStressStructureSystemic infectionTestingTranscriptTranslational RegulationTranslationsVirulenceYeastsbiological adaptation to stresschemotherapycombatenvironmental stressorexperimental studygenome-widehelicasemRNA cappingmouse modelmutantneutrophilnew therapeutic targetnovelnovel therapeutic interventionorgan transplant recipientpathogenic funguspreventprotein functionresponseribosome profilingtranslation factortreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
Candida albicans is a major human fungal pathogen responsible for a wide variety of systemic and mucosal
infections. Immunocompromised individuals, including organ transplant recipients, AIDS patients and cancer
patients on chemotherapy are highly susceptible to infection. In the host environment C. albicans encounters a
wide variety of environmental stresses, including acidic pH, osmotic/cationic, thermal, oxidative, nitrosative, cell
wall and cell membrane stresses. While transcriptional and post-translational mechanisms that mediate C.
albicans stress responses have been well-characterized, considerably less is known about the role of
translational mechanisms; given that many effective classes of antibiotics target bacterial translation
mechanisms, this remains an unexplored and unexploited avenue for antifungal development. The eIF4F
translation initiation complex is important for binding to the 5' CAP of mRNAs and contains helicase activity
that unwinds complex secondary structures in 5' untranslated regions (UTRs) to promote translation and
ribosome accessibility. We have recently demonstrated that fungal-specific C. albicans orthologs of the yeast
eIF4E-binding proteins Eap1 and Caf20, which function as negative regulators of the eIF4F complex, play an
important role in controlling oxidative and cell wall/cell membrane stress responses. In addition, we have
shown that both C. albicans proteins are down-regulated in response to membrane stress and orf19.7034 (the
Eap1 ortholog) functions as a key negative regulator of P-body formation under multiple stress conditions (P-
bodies are translationally inactive cellular compartments). Using ribosome profiling, we have also recently
demonstrated that the C. albicans morphological transition, and most likely additional virulence processes, is
under widespread global translational control. Based on this evidence, and additional studies, our hypothesis is
that elucidating translational regulatory mechanisms which control the ability of C. albicans to respond to host
environmental stresses will provide a new strategy to identify and characterize potential antifungal targets. To
address this hypothesis, we plan to: 1) determine the global translational profile of C. albicans in response to a
variety of host environmental stress conditions; we will also identify and characterize selected translationally
controlled target genes important for C. albicans stress responses, 2) determine how eIF4E-binding proteins
and components of the eIF4F complex control the ability of C. albicans to respond to host environmental
stresses, 3) determine how translational stress response mechanisms control C. albicans virulence and
pathogenicity using both a mouse model of systemic candidiasis and macrophage/neutrophil killing and
survival assays. These studies will provide a better understanding of global regulatory circuits and individual
factors that control the translational response of C. albicans to host environmental stress conditions. Ultimately,
common fungal-specific translation factors and/or target genes important for stress responses, virulence and
pathogenesis could serve as important targets for the development of novel and more effective antifungals.
项目总结/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DAVID KADOSH其他文献
DAVID KADOSH的其他文献
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{{ truncateString('DAVID KADOSH', 18)}}的其他基金
Translational Regulation of Candida glabrata Azole Resistance
光滑念珠菌唑耐药性的转化调控
- 批准号:
10681915 - 财政年份:2023
- 资助金额:
$ 58.2万 - 项目类别:
Regulation of Multidrug Resistance in the Emerging Human Fungal Pathogen Candida auris
新兴人类真菌病原体耳念珠菌的多药耐药性调控
- 批准号:
10409832 - 财政年份:2021
- 资助金额:
$ 58.2万 - 项目类别:
Regulation of Multidrug Resistance in the Emerging Human Fungal Pathogen Candida auris
新兴人类真菌病原体耳念珠菌的多药耐药性调控
- 批准号:
10317488 - 财政年份:2021
- 资助金额:
$ 58.2万 - 项目类别:
Translational Control of Morphology and Virulence in Candida albicans
白色念珠菌形态和毒力的转化控制
- 批准号:
9910361 - 财政年份:2018
- 资助金额:
$ 58.2万 - 项目类别:
Translational Control of Morphology and Virulence in Candida albicans
白色念珠菌形态和毒力的转化控制
- 批准号:
10398003 - 财政年份:2018
- 资助金额:
$ 58.2万 - 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
- 批准号:
8260211 - 财政年份:2010
- 资助金额:
$ 58.2万 - 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
- 批准号:
8463967 - 财政年份:2010
- 资助金额:
$ 58.2万 - 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
- 批准号:
8071573 - 财政年份:2010
- 资助金额:
$ 58.2万 - 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
- 批准号:
8474527 - 财政年份:2010
- 资助金额:
$ 58.2万 - 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
- 批准号:
7898091 - 财政年份:2010
- 资助金额:
$ 58.2万 - 项目类别:
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