Translational Control of Morphology and Virulence in Candida albicans
白色念珠菌形态和毒力的转化控制
基本信息
- 批准号:10398003
- 负责人:
- 金额:$ 37.8万
- 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:2018-05-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:5&apos Untranslated RegionsAIDS/HIV problemAcquired Immunodeficiency SyndromeAddressAdhesionsAgarAntifungal AgentsAntifungal TherapyCancer PatientCandida albicansCandidiasisCellsComplexCuesCytotoxic ChemotherapyDataDevelopmentDisseminated candidiasisEnzymesFilamentGastrointestinal tract structureGenesGenetic TranscriptionGoalsGrowthHumanImmunocompromised HostIn VitroIndividualInfectionKineticsLaboratoriesLifeMeasuresMediatingMicrobial BiofilmsMolecularMorphologyMucous MembraneOralOral candidiasisPathogenesisPathogenicityPatientsPlayProcessProductionPropertyPublic HealthRNAResearchRibosomesRoleSaccharomycetalesSignal PathwaySignal TransductionSiteStructureSystemic infectionTherapeutic immunosuppressionTranscriptTranslational RepressionTranslationsVaginaVirulenceVirulence FactorsYeastsbasechemotherapydesignexperimental studyfungusgenome-widemouse modelmutantneonatenovelorgan transplant recipientpathogenic funguspolysome profilingresponseribosome profilingtranscriptome sequencingyeast infection
项目摘要
PROJECT SUMMARY/ABSTRACT
Candida albicans, the most commonly isolated human fungal pathogen, is responsible for a wide variety of
systemic and mucosal infections. Immunocompromised individuals, including cancer patients on
chemotherapy, AIDS patients, neonates, and organ transplant recipients, are particularly susceptible to
infection. The ability of C. albicans to undergo a reversible morphological transition from single budding yeast
cells to filaments (elongated cells attached end-to-end) is important for virulence as well as several virulence-
related properties. While transcriptional and post-translational mechanisms that control the C. albicans
morphological transition have been well-characterized, considerably less is known about the role of
translational mechanisms. We have recently discovered that UME6, which encodes a key filament-specific
transcriptional regulator of C. albicans morphology and virulence, possesses one of the longest 5’
untranslated regions (UTRs) identified in fungi to date. The UME6 5’ UTR inhibits C. albicans filamentation
under a variety of inducing conditions as well as the ability of UME6 expression to determine C. albicans
morphology. The 5’ UTR does not affect UME6 transcript levels or induction kinetics, but instead specifically
reduces translational efficiency of UME6, as determined by a polysome profiling analysis. Importantly, the
level of translational inhibition directed by the UME6 5’ UTR is modulated by different filament-inducing
conditions. A recent preliminary ribosome profiling experiment indicates the presence of two distinct ribosome
stalling sites in the UME6 5’ UTR, both of which are located immediately upstream of predicted complex
stable RNA secondary structures. An RNA-seq analysis has demonstrated that in addition to UME6, a
significant number of C. albicans genes involved in filamentation, and a variety of other virulence-related
processes, including biofilm formation, adhesion, and secreted degradative enzyme production, also possess
long 5’ UTRs. Based on this evidence, our hypothesis is that 5’ UTR-mediated translational efficiency
mechanisms play an important role in controlling C. albicans morphology, virulence and virulence-related
processes in response to host environmental cues. In order to address this hypothesis, we plan to: 1)
determine how C. albicans filamentous growth signaling pathways control morphology and Ume6 expression
by regulating UME6 translational efficiency via the 5’ UTR, 2) determine the molecular mechanism(s) by
which the UME6 5’ UTR inhibits translational efficiency, 3) determine the broader role of 5’ UTR-mediated
translational efficiency mechanisms in controlling C. albicans virulence and a variety of virulence-related
properties. These studies will provide a better understanding of how 5’ UTR-mediated translational efficiency
mechanisms control morphology and virulence in a major human fungal pathogen. Ultimately, common
fungal-specific components of translational efficiency mechanisms that regulate fungal pathogenicity could
serve as potential targets for the development of novel and more effective antifungal strategies.
项目概要/摘要
白色念珠菌是最常见的人类真菌病原体,可导致多种疾病
全身和粘膜感染。免疫功能低下的个体,包括癌症患者。
化疗、艾滋病患者、新生儿和器官移植受者特别容易受到感染
白色念珠菌从单一芽殖酵母发生可逆形态转变的能力。
细胞与细丝(端对端连接的细长细胞)对于毒力以及多种毒力很重要-
控制白色念珠菌的转录和翻译后机制。
形态转变已被充分表征,但人们对形态转变的作用知之甚少。
我们最近发现 UME6,它编码一个关键的细丝特异性。
白色念珠菌形态和毒力的转录调节因子,拥有最长的 5’ 序列之一
迄今为止在真菌中发现的 UME6 5' UTR 抑制白色念珠菌丝状化。
在多种诱导条件下以及UME6表达能力来确定白色念珠菌
5' UTR 不影响 UME6 转录水平或诱导动力学,而是特异性影响。
通过多核糖体分析分析确定,降低了 UME6 的翻译效率。
UME6 5' UTR 指导的翻译抑制水平受不同的细丝诱导调节
最近的初步核糖体分析实验表明存在两种不同的核糖体。
UME6 5' UTR 中的停滞位点,这两个位点均位于预测复合体的直接上游
RNA-seq 分析表明,除了 UME6 之外,还有稳定的 RNA 二级结构。
大量参与丝状形成的白色念珠菌基因,以及多种其他毒力相关的基因
过程,包括生物膜形成、粘附和分泌的降解酶的产生,也具有
基于此证据,我们的假设是 5' UTR 介导的翻译效率。
机制在控制白色念珠菌形态、毒力和毒力相关方面发挥着重要作用
为了解决这个假设,我们计划:1)
确定白色念珠菌丝状生长信号通路如何控制形态和 Ume6 表达
通过 5’ UTR 调节 UME6 翻译效率,2) 通过以下方式确定分子机制
UME6 5' UTR 抑制翻译效率,3) 确定 5' UTR 介导的更广泛作用
控制白色念珠菌毒力和多种毒力相关的翻译效率机制
这些研究将有助于更好地了解 5’UTR 介导的翻译效率。
最终,控制人类主要真菌病原体的形态和毒力的机制。
调节真菌致病性的翻译效率机制的真菌特异性成分可以
作为开发新颖且更有效的抗真菌策略的潜在目标。
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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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:
$ 37.8万 - 项目类别:
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
- 批准号:
10867738 - 财政年份:2023
- 资助金额:
$ 37.8万 - 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:
$ 37.8万 - 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:
$ 37.8万 - 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:
$ 37.8万 - 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:
$ 37.8万 - 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:
$ 37.8万 - 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:
$ 37.8万 - 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:
$ 37.8万 - 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:
8648982 - 财政年份:2010
- 资助金额:
$ 37.8万 - 项目类别:
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