ROLE OF CELL WALL INTEGRITY IN ECHINOCANDIN RESISTANCE IN C. NEOFORMANS
细胞壁完整性在新型隐球菌棘白菌素抗性中的作用
基本信息
- 批准号:9927587
- 负责人:
- 金额:$ 38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-26 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:Africa South of the SaharaAmphotericin BAnabolismAntifungal AgentsAntifungal TherapyAntiviral AgentsAreaBiochemicalCandidate Disease GeneCell CommunicationCell MaintenanceCell WallCellsCessation of lifeCryptococcosisCryptococcusCryptococcus neoformansCyclic AMPCyclic AMP-Dependent Protein KinasesDataDefectDetectionDevelopmentDiseaseDrug TargetingFluconazoleFutureGene ActivationGene DeletionGene ProteinsGene TargetingGenesGeneticGenetic TranscriptionGenomicsGlucansGoalsHIVHIV SeropositivityHeat-Shock ResponseHomeostasisHumanImmunocompromised HostIndividualInfectionLeadMaintenanceMammalsMeasurableMolecularNatural ResistanceNew AgentsOxidative StressPathway AnalysisPathway interactionsPatientsPhenotypePhosphotransferasesPlayProtein KinaseProtein Kinase CProteinsRegulationRegulatory PathwayRelapseResistanceRoleSignal PathwayStressStructural ProteinToxic effectTuberculosisVirulenceburden of illnesscapsulecell growth regulationdeletion librarydesignechinocandin resistanceenzyme structurefungusgenetic regulatory proteinhuman pathogeninhibitor/antagonistmortalitynitrosative stressnovelnovel therapeuticspathogenic funguspreventrepairedresponsescreeningsynergismtranscription factor
项目摘要
Abstract:
Cryptococcus neoformans is a pathogenic fungus that is found world-wide and causes meningioencephalitis,
particularly in immunocompromised individuals. It is invariably fatal unless treated, and the current antifungals
are inadequate to effectively cure this disease, due to inherent toxicities, the inability to kill the fungus and
prevent relapse, or innate resistance to the class of antifungals. Recent studies have indicated that there are
over 1,000,000 new cases of cryptococcosis in the world each year, which results in over 600,000 deaths.
New agents to treat Cryptococcus are needed, and the fungal cell wall is an attractive target, since it is unique
to fungi and absent in humans.
Echinocandins are a class of antifungals that target glucan synthesis in the cell wall. Cryptococcus is naturally
resistant to the echinocandins. We have shown that disruption of the cell wall integrity (CWI) signaling pathway
causes Cryptococcus to become highly sensitive to echinocandins, and identified candidate transcription
factors that may play a role in echinocandin resistance. This pathway is the major pathway that impacts cell
wall and is dependent on protein kinase C (Pkc1). The CWI/PKC1 pathway plays a key role in response to
heat shock, oxidative and nitrosative stress, and cell wall inhibitors. Our preliminary data suggests that this
pathway is part of a highly connected network that controls cell wall biosynthesis, repair and remodeling. The
major goal of this project is to define the mechanism(s) by which cell wall integrity is maintained in response to
specific cell wall inhibitors, including echinocandins and to identify potential gene targets for antifungals with
synergy to echinocandins. There are three specific aims:
In the first aim, we will define the role of the cell wall integrity pathway in echinocandin resistance using
genomic and network analysis approaches. In the second aim, we will identify the genes essential to cell wall
integrity and that contribute to echinocandin resistance by screening large deletion sets for specific
phenotypes. In the third aim, we will assess the functional interactions of the cell wall integrity components.
In this highly collaborative project, we propose to use our complementary expertise to integrate genetic,
phenotypic and biochemical data to identify and characterize the network of interactions governing cell wall
homeostasis in C. neoformans. This will significantly advance our understanding of cell wall maintenance and
remodeling in a human pathogen and will provide multiple targets for designing specific antifungal drugs that
are less likely to be toxic in mammals.
抽象的:
隐孢子虫是一种致病的真菌,在世界范围内发现,并引起脑膜脑炎,
特别是在免疫功能低下的个体中。除非治疗,否则它总是致命的,而当前的抗真菌剂
由于固有的毒性,无法杀死真菌,因此无法有效治愈这种疾病
防止复发或对抗真菌类别的先天抵抗。最近的研究表明
每年,全球有超过1,000,000例新的隐球菌病病例,导致超过600,000例死亡。
需要新的治疗加密环球的代理,而真菌细胞壁是一个有吸引力的目标,因为它是独特的
真菌和人类缺席。
棘突是靶向细胞壁中葡聚糖合成的一类抗真菌蛋白。加密环球自然是
对棘突的抗性。我们已经证明了细胞壁完整性(CWI)信号通路的破坏
导致加密摄氏对echinocandins高度敏感,并确定了候选转录
可能在eChinocandin抗性中起作用的因素。该途径是影响细胞的主要途径
壁,取决于蛋白激酶C(PKC1)。 CWI/PKC1途径在响应于
热休克,氧化和亚硝化应激以及细胞壁抑制剂。我们的初步数据表明这一点
途径是控制细胞壁生物合成,修复和重塑的高度连接网络的一部分。这
该项目的主要目标是定义响应细胞壁完整性的机制
特定的细胞壁抑制剂,包括echinocandins,并确定具有抗真菌抗体的潜在基因靶标
与echinocandins协同作用。有三个特定的目标:
在第一个目的中,我们将使用使用的细胞壁完整性途径在使用echinocandin抗性中的作用
基因组和网络分析方法。在第二个目标中,我们将确定细胞壁必不可少的基因
完整性和通过筛选特定的大删除集来促进eChinocandin的抗性
表型。在第三个目标中,我们将评估细胞壁完整性成分的功能相互作用。
在这个高度协作的项目中,我们建议利用我们的补充专业知识来整合遗传,
表型和生化数据,以识别和表征控制细胞壁的相互作用网络
C. Neoformans中的体内平衡。这将大大提高我们对细胞墙维护和
在人类病原体中进行重塑,并将提供多个目标,用于设计特定的抗真菌药物
在哺乳动物中不太可能有毒。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Maureen J Donlin其他文献
Maureen J Donlin的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Maureen J Donlin', 18)}}的其他基金
ROLE OF CELL WALL INTEGRITY IN ECHINOCANDIN RESISTANCE IN C. NEOFORMANS
细胞壁完整性在新型隐球菌棘白菌素抗性中的作用
- 批准号:
9237001 - 财政年份:2017
- 资助金额:
$ 38万 - 项目类别:
ROLE OF CELL WALL INTEGRITY IN ECHINOCANDIN RESISTANCE IN C. NEOFORMANS
细胞壁完整性在新型隐球菌棘白菌素抗性中的作用
- 批准号:
10626232 - 财政年份:2017
- 资助金额:
$ 38万 - 项目类别:
ANALYSIS OF MUTATOR TRANSPOSON DEVELOPMENTAL REGULATION
突变转座子发育调控分析
- 批准号:
2170370 - 财政年份:1993
- 资助金额:
$ 38万 - 项目类别:
相似国自然基金
HAT1通过调控ERG11琥珀酰化修饰增强克柔念珠菌两性霉素B耐药性的机制研究
- 批准号:82304037
- 批准年份:2023
- 资助金额:30.00 万元
- 项目类别:青年科学基金项目
线粒体抑制希木龙念珠菌活性氧损伤介导其对两性霉素B耐药的机制研究
- 批准号:82372274
- 批准年份:2023
- 资助金额:49.00 万元
- 项目类别:面上项目
构建递送两性霉素B的聚丝氨酸脂质纳米粒用于增强抗真菌感染治疗效果的研究
- 批准号:
- 批准年份:2022
- 资助金额:30 万元
- 项目类别:青年科学基金项目
固醇衍生物Eldecalcitol对两性霉素B增效减毒活性及机制研究
- 批准号:82202545
- 批准年份:2022
- 资助金额:30.00 万元
- 项目类别:青年科学基金项目
固醇衍生物Eldecalcitol对两性霉素B增效减毒活性及机制研究
- 批准号:
- 批准年份:2022
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Antifungals targeting pantothenate phosphorylation
靶向泛酸磷酸化的抗真菌药
- 批准号:
10696567 - 财政年份:2023
- 资助金额:
$ 38万 - 项目类别:
Development of a novel broad spectrum antifungal therapeutic targeting Glycosylphosphatidylinositol (GPI) biosynthesis and cell wall biogenesis
开发一种针对糖基磷脂酰肌醇 (GPI) 生物合成和细胞壁生物合成的新型广谱抗真菌治疗药物
- 批准号:
10759723 - 财政年份:2023
- 资助金额:
$ 38万 - 项目类别:
A Biosynthetic Strategy to Manufacture Less Toxic Amphotericins
生产毒性较小的两性霉素的生物合成策略
- 批准号:
10383158 - 财政年份:2021
- 资助金额:
$ 38万 - 项目类别:
Resistance-gene-guided genome mining for novel antifungal compounds
抗性基因引导的新型抗真菌化合物基因组挖掘
- 批准号:
10368095 - 财政年份:2021
- 资助金额:
$ 38万 - 项目类别:
ROLE OF CELL WALL INTEGRITY IN ECHINOCANDIN RESISTANCE IN C. NEOFORMANS
细胞壁完整性在新型隐球菌棘白菌素抗性中的作用
- 批准号:
9237001 - 财政年份:2017
- 资助金额:
$ 38万 - 项目类别: