Genetics of fungal persistence and pathogenicity in mammalian hosts
哺乳动物宿主中真菌持久性和致病性的遗传学
基本信息
- 批准号:10874018
- 负责人:
- 金额:$ 62.4万
- 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:2023-08-17 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAffectAllelesAntifungal TherapyBar CodesBlood - brain barrier anatomyBody TemperatureBrainCRISPR/Cas technologyCandida albicansCandidate Disease GeneCellsChromosome MappingClinicalCloningCre-LoxPDataDevelopmentDiploidyDissectionGene ExpressionGenesGeneticGenotypeHaploidyHealth BenefitHeritabilityHeterozygoteHigh temperature of physical objectHumanHuman bodyImageInfectionInvadedInvestigationKidneyLifeLiverMammalsMapsMediatingMeiosisMicroscopyModelingMolecularMorphologyMusMycosesNecrosisOrganPartner in relationshipPathogenesisPathogenicityPenetrationPhenotypePhysiologicalPopulationProtocols documentationRoleSaccharomyces cerevisiaeSaccharomycetalesSamplingShapesSocietiesSourceSpleenSurfaceTestingTissuesVariantWorkYeast Model SystemYeastscandidate identificationcausal variantclinically relevantdesignexperimental studyfollow-upfungal geneticsfungusgene cloninggenetic varianthuman pathogeninsightmicrobialmodel organismopportunistic pathogenpathogenic funguspleiotropismtranscriptome sequencing
项目摘要
Project Summary
Opportunistic fungal infections can be life-threatening and difficult to treat. Identifying the
genetic and molecular mechanisms that enable fungi to persist in humans could have major
health benefits for society, potentially even enabling the development of more effective
antifungal therapies. The model organism Saccharomyces cerevisiae is itself an opportunistic
human pathogen, with many strains isolated from clinical infections. The ability to infect and
persist within humans is not universal among S. cerevisiae strains. Clinical S. cerevisiae
isolates tend to be highly heterozygous diploids that can grow at higher temperatures and
invade into surfaces. However, rigorous genetic dissection of S. cerevisiae’s persistence and
pathogenicity within mammalian hosts is needed. To begin such work, we used chromosomally-
encoded barcodes and lineage tracking to phenotype a panel of genotyped haploid progeny
from a budding yeast cross in mice. The specific cross employed was between a haploid
derivative of a clinical isolate and the reference strain. Linkage mapping identified dozens of loci
influencing fungal persistence within a mammalian host, many of which lack previously identified
candidate genes and show host organ-dependent effects. Following our work, major questions
remain unanswered, including the genetic, molecular, and physiological mechanisms underlying
yeast persistence and yeast-host interactions; how alleles at causal loci shape the phenotypes
of highly heterozygous diploids resembling clinical isolates; the role of surface attachment and
invasion in persistence and pathogenicity; and whether the effects of causal loci contributing to
fungal pathogenicity have effects that depend on host genotype. Here, we will extend our work
by (1) studying mechanisms causing yeast persistence in particular organs by cloning causal
genes in yeast, as well as by using cutting-edge microscopy and RNA-seq to analyze yeast-host
interactions; (2) testing how combinations of pathogenicity alleles combine in highly
heterozygous diploid yeast strains; (3) analyzing how the ability to attach to and invade into
surfaces influences the pathogenicity of cross progeny; and (4) examining the genetics of fungal
pathogenicity across genetically distinct mouse hosts. Our proposal will utilize the untapped
potential of the budding yeast model system to provide concrete insights into the genetics and
molecular mechanisms underlying opportunistic fungal pathogenicity.
项目总结
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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Ian Michael Ehrenreich其他文献
Ian Michael Ehrenreich的其他文献
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{{ truncateString('Ian Michael Ehrenreich', 18)}}的其他基金
Characterizing the complex underpinnings of genetic background effects
描述遗传背景效应的复杂基础
- 批准号:
10316997 - 财政年份:2019
- 资助金额:
$ 62.4万 - 项目类别:
Characterizing the complex underpinnings of genetic background effects
描述遗传背景效应的复杂基础
- 批准号:
10544341 - 财政年份:2019
- 资助金额:
$ 62.4万 - 项目类别:
Comprehensive dissection of higher-order genetic interactions
高阶遗传相互作用的全面剖析
- 批准号:
9282754 - 财政年份:2014
- 资助金额:
$ 62.4万 - 项目类别:
Comprehensive dissection of higher-order genetic interactions
高阶遗传相互作用的全面剖析
- 批准号:
8674821 - 财政年份:2014
- 资助金额:
$ 62.4万 - 项目类别:
Comprehensive dissection of higher-order genetic interactions
高阶遗传相互作用的全面剖析
- 批准号:
8850465 - 财政年份:2014
- 资助金额:
$ 62.4万 - 项目类别:
Genetic basis and pathogenicity of invasive growth in yeast
酵母菌侵袭性生长的遗传基础和致病性
- 批准号:
8618629 - 财政年份:2013
- 资助金额:
$ 62.4万 - 项目类别:
Genetic basis and pathogenicity of invasive growth in yeast
酵母菌侵袭性生长的遗传基础和致病性
- 批准号:
8776919 - 财政年份:2013
- 资助金额:
$ 62.4万 - 项目类别:
Defining the genomic architecture of expression quantitative traits
定义表达数量性状的基因组结构
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7748265 - 财政年份:2009
- 资助金额:
$ 62.4万 - 项目类别:
Defining the genomic architecture of expression quantitative traits
定义表达数量性状的基因组结构
- 批准号:
7915671 - 财政年份:2009
- 资助金额:
$ 62.4万 - 项目类别:
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