Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens
主要细菌病原体中脂质毒力因子的化学生物学发现
基本信息
- 批准号:10518252
- 负责人:
- 金额:$ 64.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-22 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAutophagocytosisBacteriaBacterial ChromosomesBiologicalBiological ProcessBiologyCatalogsCell modelCellsCellular AssayChemical StructureChemicalsChromosome MappingCommunicable DiseasesCord FactorsDataDatabasesDetectionDevelopmentDiagnosisDiseaseEnteralEnvironmentEvolutionFeedbackFoamy MacrophageFunctional disorderGene DeletionGenerationsGenesGenomicsGenus MycobacteriumGram-Negative BacteriaHourHumanImmune responseImmunologic ReceptorsInfectionInfectious Diseases ResearchLaboratoriesLinkLipidsLiteratureLocationLysosomesMapsMass Spectrum AnalysisMeasuresMediatingMembraneMethodsModernizationMolecularMusMycobacterium tuberculosisNamesNatureNucleosidesNutrientOrganismPatientsPhenotypePhospholipidsProcessProductionProteinsProteomicsRoleSalmonellaSalmonella entericaSalmonella typhiScienceSignal TransductionStudy SectionSystemT cell responseTestingTranscriptVirulenceVirulence FactorsVirulentWhole Organismbasecomparativecomparative genomicsexperienceexperimental studyforward geneticsgene discoverygene functiongenetic approachin vivoinhibitorinsightlipidomelipidomicsmacrophagemetabolomicsmycobacterialnovel strategiesoverexpressionpathogenpathogenic bacteriaprenylreceptorresponsereverse geneticsselective expressionsuccesstooltranscriptomicstranslational study
项目摘要
Project Summary
Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens
For decades, the search for the causes of bacterial virulence has focused on genes rather than metabolites.
Genetic approaches have been broadly successful, and modern infectious disease research relies
fundamentally on genomic maps of the major pathogens. Owing to the lack of whole-organism chemical
biology tools, bacterial lipids have not been systematically tested for their roles in virulence, even though lipids
are the primary interface with the human host, where they control nutrient flow and trigger host immune
response. We invented a mass spectrometry platform for lipid profiling to detect nearly all ionizable lipids in a
bacterial cell within 2 hours. Experiments on Mycobacterium tuberculosis and Salmonella enterica serovar
Typhi now provide clear evidence for the general insight that many, perhaps the majority, of lipids in the world's
bacterial pathogens, are currently unknown as named compounds. Based on successes in identifying virulence
factors in two major pathogens of worldwide significance, we will carry out a chemical biology approach known
as forward lipidomics. Specifically, we will use whole organism mass spectrometry profiling to discover the
lipids that are selectively expressed in virulent bacteria and are unknown in existing lipid catalogs. Then, we
will chemically synthesize the virulence associated lipids and link them to their biosynthetic genes for deletion
in bacteria using reverse genetic approaches. Using genetically modified bacteria that are deficient in defined
lipids, we will determine the roles of virulence lipids during infection. Using nature identical synthetic lipids, we
will determine the cellular mechanisms of generation of foamy macrophages and identify immune receptors
that mediate host response. We will create lipid maps of the major Gram negative pathogen groups based on
patient strains to build the overlooked field of chemical biology of bacterial virulence. These basic and
translational studies will support the development new forward lipidomics approaches to the diagnosis and
treatment of major infectious diseases.
项目摘要
主要致病菌中脂类毒力因子的化学生物学发现
几十年来,寻找细菌毒力的原因一直集中在基因上,而不是代谢物上。
基因方法在很大程度上是成功的,现代传染病研究依靠
基本上取决于主要病原体的基因组图谱。由于缺乏全生物体的化学物质
生物学工具,细菌脂类还没有系统地测试它们在毒力中的作用,即使脂类
是与人类宿主的主要接口,在那里它们控制营养流动并触发宿主免疫
回应。我们发明了一种用于脂类分析的质谱学平台,可以检测几乎所有可电离的脂类
细菌细胞在2小时内。结核分枝杆菌和肠道沙门氏菌血清型的实验研究
伤寒现在为普遍的洞察力提供了明确的证据,即世界上许多,也许是大多数的脂质
细菌病原体,目前作为命名化合物尚不为人所知。基于在鉴定毒力方面的成功
在两种具有世界意义的主要病原体因素中,我们将开展一种已知的化学生物学方法
这是一种前沿性的脂质组学。具体地说,我们将使用整个生物体的质谱图来发现
在致病细菌中选择性表达的脂类,在现有的脂类目录中未知。然后,我们
将化学合成与毒力相关的脂类,并将它们与其生物合成基因联系起来进行删除
在使用反向遗传方法的细菌中。使用定义有缺陷的转基因细菌
脂类,我们将确定毒力类脂在感染过程中的作用。使用天然相同的合成脂类,我们
将确定泡沫巨噬细胞产生的细胞机制并识别免疫受体
这是宿主反应的中介。我们将根据以下内容创建主要革兰氏阴性病原菌群的脂谱
患者菌株构建了被忽视的细菌毒力化学生物学领域。这些基本的和
翻译研究将支持开发新的正向脂组学方法来诊断和
重大传染病的救治。
项目成果
期刊论文数量(0)
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{{ truncateString('DAVID Branch MOODY', 18)}}的其他基金
Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens
主要细菌病原体中脂质毒力因子的化学生物学发现
- 批准号:
10651853 - 财政年份:2022
- 资助金额:
$ 64.25万 - 项目类别:
Study of M. tuberculosis under human host selection to identify virulence and barrier lipids (Project 1)
研究人类宿主选择下的结核分枝杆菌以确定毒力和屏障脂质(项目 1)
- 批准号:
10612035 - 财政年份:2021
- 资助金额:
$ 64.25万 - 项目类别:
Metabolic adaptions of Mycobacterium tuberculosis at diverse host-pathogen interfaces
结核分枝杆菌在不同宿主-病原体界面的代谢适应
- 批准号:
10630740 - 财政年份:2021
- 资助金额:
$ 64.25万 - 项目类别:
Metabolic determinants of Mtb virulence, vulnerability and variation
结核分枝杆菌毒力、脆弱性和变异的代谢决定因素
- 批准号:
10438911 - 财政年份:2021
- 资助金额:
$ 64.25万 - 项目类别:
Metabolic determinants of Mtb virulence, vulnerability and variation
结核分枝杆菌毒力、脆弱性和变异的代谢决定因素
- 批准号:
10612023 - 财政年份:2021
- 资助金额:
$ 64.25万 - 项目类别: