Comparative and functional genomics of C. neoformans
新型隐球菌的比较和功能基因组学
基本信息
- 批准号:8616150
- 负责人:
- 金额:$ 28.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-08-01 至 2019-02-28
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAcquired Immunodeficiency SyndromeAffinityAnabolismAntifungal AgentsAzolesBreathingCell Surface ProteinsCell surfaceCenters for Disease Control and Prevention (U.S.)CryptococcusCryptococcus neoformansCryptococcus neoformans infectionDefectDiseaseDrug usageEndocytosisEnvironmentErgosterolEvaluationFundingGenesGoalsGrowthHIVHemeHeme IronHemoglobinHumanImmune systemImmunityImmunocompetentIn VitroInfectionInfection ControlInsertional MutagenesisIronIron-Binding ProteinsKnowledgeLeadLifeMammalsMelaninsMeningoencephalitisMetalloporphyrinsMetalsModelingMolecularMusMutationMycosesNutrientNutritionalPathogenesisPatientsPharmaceutical PreparationsPolysaccharidesPredispositionProcessProteinsProtoporphyrinsRecyclingRegulationRelative (related person)ResearchResistanceRewardsRoleSourceSystemTestingTherapeuticToxic effectVacuoleVirulenceVirulence Factorscapsulecombatcomparative genomicsdisorder preventionextracellularfunctional genomicsfungusheme-binding proteiniron (III) reductasemacrophagemannoproteinsmutantnovelnovel therapeuticspandemic diseasepathogenpublic health relevanceresponsetherapeutic targettraffickingtraituptake
项目摘要
Project Summary/Abstract. The pathogenic fungus Cryptococcus neoformans causes life-threatening
infections in AIDS patients and therefore poses a major threat to the >34 million people worldwide who are
infected with HIV. The related species Cryptococcus gattii has recently emerged as a primary pathogen of
immunocompetent people. The long-term goal of this project is to acquire knowledge that will lead to new
strategies to combat fungal infections. In particular, we want to establish a detailed understanding of the
factors required for pathogen growth in mammalian hosts and identify useful targets for therapy. In this
regard, iron availability is a key indicator of the host environment as well as an essential nutrient for
pathogen proliferation. In addition, mammals actively withhold iron from pathogens in a process termed
nutritional immunity, and pathogens must therefore aggressively compete for iron. Iron is particularly
important for the pathogenesis of C. neoformans because the availability of this metal not only influences
growth but also the size of the polysaccharide capsule that is the major virulence factor. To fill gaps in our
understanding of the mechanisms by which fungal pathogens compete for iron, the first specific aim is to
determine the molecular functions of cell surface proteins that support iron acquisition from heme. These
proteins each contribute to robust growth on heme and include a secreted mannoprotein that is a candidate
heme-binding protein as well as three ferric reductases. A second specific aim will characterize the
intracellular machinery for heme trafficking and processing. An insertional mutagenesis screen identified 25
genes in which mutations caused growth defects on heme, and some of these genes encode intracellular
trafficking machinery. This result led to the hypothesis that heme is acquired by endocytosis and
transported to the vacuole for iron extraction and recycling. Mutants with defects at specific steps in known
and candidate transport functions will be constructed and tested for their ability to process heme. A final
specific aim will evaluate the role of heme and iron acquisition functions in the virulence of C. neoformans.
Mutants lacking combinations of iron acquisition functions will be tested in mouse inhalation models of
cryptococcosis and the proliferation of the mutants in macrophages will be examined in the context of
different iron sources. These studies will provide a comprehensive view of the relative importance of
specific host iron sources and fungal uptake strategies during cryptococcosis.
!
项目摘要/摘要。致病真菌新型隐球菌会危及生命
艾滋病患者感染,因此对全世界超过 3400 万人构成重大威胁
感染艾滋病毒。相关物种格特隐球菌最近已成为主要病原体
免疫能力强的人。该项目的长期目标是获取能够带来新知识的知识
对抗真菌感染的策略。特别是,我们希望对以下内容有一个详细的了解:
病原体在哺乳动物宿主中生长所需的因素,并确定有用的治疗靶点。在这个
就铁的可用性而言,铁的可用性是宿主环境的关键指标,也是生命体的必需营养素。
病原体增殖。此外,哺乳动物会主动从病原体中截留铁,这一过程被称为
因此,病原体必须积极竞争铁。铁尤其
对于新型隐球菌的发病机制很重要,因为这种金属的可用性不仅影响
生长还与多糖荚膜的大小有关,多糖荚膜是主要的毒力因子。填补我们的空白
了解真菌病原体竞争铁的机制,第一个具体目标是
确定支持从血红素获取铁的细胞表面蛋白的分子功能。这些
每种蛋白质都有助于血红素的强劲生长,其中包括一种候选的分泌性甘露糖蛋白
血红素结合蛋白以及三种铁还原酶。第二个具体目标将描述
血红素运输和加工的细胞内机制。插入诱变筛选确定了 25
突变导致血红素生长缺陷的基因,其中一些基因编码细胞内
贩运机器。这一结果导致了血红素是通过内吞作用获得的假设
运输到液泡进行铁提取和回收。已知特定步骤有缺陷的突变体
将构建候选运输功能并测试其处理血红素的能力。决赛
具体目标将评估血红素和铁获取功能在新型隐球菌毒力中的作用。
缺乏铁获取功能组合的突变体将在小鼠吸入模型中进行测试
隐球菌病和巨噬细胞中突变体的增殖将在以下背景下进行检查
不同的铁源。这些研究将提供关于相对重要性的全面看法。
隐球菌病期间的特定宿主铁来源和真菌摄取策略。
!
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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JAMES W KRONSTAD其他文献
JAMES W KRONSTAD的其他文献
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{{ truncateString('JAMES W KRONSTAD', 18)}}的其他基金
Chromosome copy number variation and AIDS-associated cryptococcosis
染色体拷贝数变异和艾滋病相关隐球菌病
- 批准号:
7767005 - 财政年份:2009
- 资助金额:
$ 28.38万 - 项目类别:
Chromosome copy number variation and AIDS-associated cryptococcosis
染色体拷贝数变异和艾滋病相关隐球菌病
- 批准号:
7679357 - 财政年份:2009
- 资助金额:
$ 28.38万 - 项目类别:
Comparative and functional genomics of C. neoformans
新型隐球菌的比较和功能基因组学
- 批准号:
6850675 - 财政年份:2003
- 资助金额:
$ 28.38万 - 项目类别:
Comparative and functional genomics of C. neoformans
新型隐球菌的比较和功能基因组学
- 批准号:
8416255 - 财政年份:2003
- 资助金额:
$ 28.38万 - 项目类别:
Comparative and functional genomics of C. neoformans
新型隐球菌的比较和功能基因组学
- 批准号:
7009067 - 财政年份:2003
- 资助金额:
$ 28.38万 - 项目类别:
Comparative and functional genomics of C. neoformans
新型隐球菌的比较和功能基因组学
- 批准号:
7578170 - 财政年份:2003
- 资助金额:
$ 28.38万 - 项目类别:
Comparative and functional genomics of C. neoformans
新型隐球菌的比较和功能基因组学
- 批准号:
9020184 - 财政年份:2003
- 资助金额:
$ 28.38万 - 项目类别:
Comparative and functional genomics of C. neoformans
新型隐球菌的比较和功能基因组学
- 批准号:
8013310 - 财政年份:2003
- 资助金额:
$ 28.38万 - 项目类别:
Comparative and functional genomics of C. neoformans
新型隐球菌的比较和功能基因组学
- 批准号:
7758330 - 财政年份:2003
- 资助金额:
$ 28.38万 - 项目类别:
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