Regulation of the virulence factor PlcH in Pseudomonas aeruginosa
铜绿假单胞菌毒力因子PlcH的调控
基本信息
- 批准号:10884588
- 负责人:
- 金额:$ 37.88万
- 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:2023-08-18 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:BetaineBiologicalCellsCholineCystic FibrosisDataDiseaseEnvironmentEpithelial CellsEvolutionFunctional disorderGene Expression RegulationGeneticGenetic TranscriptionGlycineHealthHomeostasisHumanIndividualInfectionIronKnowledgeLeftLungLung infectionsMetabolic PathwayMetabolismMiltefosineMissionModelingMusMutationOxygenPathogenesisPathway interactionsPersonsPhospholipase CPhospholipidsPilumPlayPositioning AttributePost-Translational RegulationProcessProductionPseudomonas aeruginosaPulmonary Cystic FibrosisPulmonary SurfactantsRegulationRegulatory PathwayRepressionResearchRoleSeverity of illnessSignal TransductionSiteSphingolipidsSphingomyelinaseSphingosineStarvationSystemTestingTitrationsTranscriptional RegulationTreatment EfficacyType III Secretion System PathwayType IV Secretion System PathwayUnited States National Institutes of HealthVirulenceVirulence FactorsWorkbiochemical toolscell typedetection platformdimethylglycinedrug repurposingexperienceextracellularhuman diseasehuman pathogeninorganic phosphateinsightmutantnovelpathogenperiplasmsurfactanttargeted treatmenttherapeutic targettissue culture
项目摘要
Pseudomonas aeruginosa (Pa) is an important opportunistic human pathogen that deploys a variety of virulence
factors, each playing roles in different infection sites or with different cell types. One important virulence factor
of Pa is the hemolytic phospholipase C/sphingomyelinase, PlcH. plcH mutants are defective in a wide range of
infection models and PlcH expression by strains has been correlated to human disease severity and differential
treatment efficacy. There are three currently known inputs to PlcH expression: induction by phosphate starvation,
induction by glycine betaine, and repression by low oxygen environments. While each of these regulatory paths
have been described, there remain important gaps in our understanding of PlcH regulation as well as alterations
in these regulatory pathways in specific disease contexts. In this proposal, we will determine the identity and
mechanisms of previously unidentified transcriptional and posttranslational regulation of PlcH and determine the
role of altered PlcH regulation during Pa adaptation in the lungs of people with cystic fibrosis.
Despite the contribution of PlcH to Pa virulence, study of its regulation lags behind that of other virulence factors.
Here we present preliminary data for novel transcriptional regulation of plcH, identification of a new post-
translational PlcH regulatory step, and present changes to metabolic pathways directly upstream of plcH
induction that occur within the cystic fibrosis lung. Our hypothesis is that PlcH production and export is regulated
at multiple levels and that these regulatory steps work to titrate the flux of enzymatic products and to avoid
damage to producing cells. We have longstanding experience with PlcH and a large experimental toolkit with
which to approach its regulation. We are well positioned to understand the mechanisms behind uncharacterized
PlcH regulatory pathways and to identify new regulatory inputs. We will address PlcH regulation by (i)
determining the mechanisms of uncharacterized plcH transcriptional regulation and the importance of each
mechanism of transcriptional induction, (ii) deciphering post-translational control mechanisms for PlcH, and (iii)
examining alteration in PlcH expression by pathoadaptive mutations occurring during long term cystic fibrosis
lung infections.
The work proposed here will allow us to have a more complete understanding of PlcH regulation, providing
biological insight and exposing potential targets for inhibition of PlcH production.
铜绿假单胞菌(Pa)是一种重要的机会性人类病原体,具有多种毒力
项目成果
期刊论文数量(0)
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MATTHEW J WARGO的其他文献
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{{ truncateString('MATTHEW J WARGO', 18)}}的其他基金
Pseudomonas detection and metabolism of sphingosine
假单胞菌检测和鞘氨醇代谢
- 批准号:
8581641 - 财政年份:2012
- 资助金额:
$ 37.88万 - 项目类别:
Pseudomonas detection and metabolism of sphingosine
假单胞菌检测和鞘氨醇代谢
- 批准号:
8760307 - 财政年份:2012
- 资助金额:
$ 37.88万 - 项目类别:
Pseudomonas detection and metabolism of sphingosine
假单胞菌检测和鞘氨醇代谢
- 批准号:
9170956 - 财政年份:2012
- 资助金额:
$ 37.88万 - 项目类别:
Pseudomonas detection and metabolism of sphingosine
假单胞菌检测和鞘氨醇代谢
- 批准号:
8417470 - 财政年份:2012
- 资助金额:
$ 37.88万 - 项目类别:
VERMONT COBRE PROJECT 7: BETAINE REGULATION OF PSEUDOMONAS VIRULENCE
佛蒙特州 COBRE 项目 7:甜菜碱对假单胞菌毒力的调节
- 批准号:
8360778 - 财政年份:2011
- 资助金额:
$ 37.88万 - 项目类别:
CHARACTERIZATION OF PSEUDOMONAS PHOSPHOLIPASES INVOLVED IN VIRULENCE
参与毒力的假单胞菌磷脂酶的表征
- 批准号:
8168184 - 财政年份:2010
- 资助金额:
$ 37.88万 - 项目类别:
VERMONT COBRE PROJECT 7: BETAINE REGULATION OF PSEUDOMONAS VIRULENCE
佛蒙特州 COBRE 项目 7:甜菜碱对假单胞菌毒力的调节
- 批准号:
8167737 - 财政年份:2010
- 资助金额:
$ 37.88万 - 项目类别:
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