Novel cytoskeletal mechanisms of pathogenic bacteria interactions with intestinal epithelium
病原菌与肠上皮相互作用的新细胞骨架机制
基本信息
- 批准号:10516636
- 负责人:
- 金额:$ 50.68万
- 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:2022-07-15 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:ActinsAntibiotic TherapyAttenuatedAutomobile DrivingBacteriaBacterial AdhesionBacterial Antibiotic ResistanceBacterial Attachment SiteBacterial InfectionsCRISPR/Cas technologyCell CommunicationCell LineCell surfaceCellsChemicalsChronicCitrobacter rodentiumCytoskeletonDataDiseaseEconomic BurdenElderlyEnteralEpithelialEpithelial CellsEscherichia coliEscherichia coli EHECEventFilamentGastroenteritisGastrointestinal DiseasesGenesGeneticHealthHemolytic-Uremic SyndromeHumanImmunocompromised HostIn VitroInfantInfectionInflammatoryInflammatory Bowel DiseasesIntestinal DiseasesIntestinal MucosaInvadedKnock-outKnockout MiceMediatingMicrofilamentsModelingMolecularMolecular ChaperonesMorbidity - disease rateMotorMotor ActivityMusMyosin ATPaseMyosin Type IIOrganoidsOutcomePathogenesisPathogenicityPathway interactionsPatientsPersonsPharmacologyPlayPreventionProcessProtein IsoformsProteinsPublic HealthRNA InterferenceRegulationRoleRouteSalmonellaSalmonella entericaSeveritiesShigellaSymptomsSystemic diseaseTestingTherapeutic InterventionTransgenic MiceUrsidae Familybaseblebbistatincohortcrosslinkenteric infectionenteric pathogenenteropathogenic Escherichia coligastrointestinalgenetic approachgenetic manipulationgut colonizationimprovedin vivoinhibitorinnovationinsightintestinal epitheliummonolayermortalitymutantnew therapeutic targetnon-muscle myosinnovelnovel therapeutic interventionnovel therapeuticspathogenpathogenic bacteriapolymerizationreceptor
项目摘要
ABSTRACT
Intestinal Epithelial Cells (IEC) provide the first line of defense against enteric pathogenic bacteria. However
bacterial pathogens developed different strategies to colonize intestinal epithelium causing severe
gastrointestinal disorder. One strategy, used by ‘attaching and effacing’ bacteria (AEB), such as
enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC), involves bacterial adhesion to IEC
without entering the host cells. The other strategy used by adherent Invasive E. coli (AIEC) or Salmonella
results in bacterial internalization into IEC. These different colonization routes bear a key mechanistic
similarity: they require rearrangements of the epithelial actin cytoskeleton to enable bacterial attachment and
invasion. One important but understudied mechanism of pathogen-induced cytoskeletal remodeling involves a
major actin cytoskeleton motor, non-muscle myosin II (NM-II). Our preliminary data demonstrate a striking
dualism of NM-II-dependent regulation of bacterial-IEC interactions. Pharmacologic and genetic inhibition of
NM-II increases AEB attachment to IEC, but inhibits AIEC invasion in vitro and in vivo. These contrasting roles
of NM-II in IEC-bacterial interactions likely reflect exploiting two different NM II-dependent functions: its actin
filament contractility and actin filament cross-linking activity, by different pathogens. This exciting data provides
a scientific premise for the following innovative hypothesis: NM-II plays a dual role in regulating enteric
pathogen interactions with intestinal epithelium by inhibiting AEB attachment to epithelial cells, but
promoting epithelial entry of invading pathogenic bacteria.
This hypothesis will be tested in the following Aims: (1) to determine the roles of NM-II in regulating intestinal
epithelial cell interactions with attaching and effacing bacteria; (2) to dissect the mechanisms of NM-II-driven
internalization of invading bacteria into intestinal epithelial cells. We will study EPEC, EHEC, AIEC and
Salmonella colonization of model IEC cell lines, organoid-derived IEC monolayers in vitro and intestinal
colonization by Citrobacter rodentium, AIEC and Salmonella in vivo. NM-II activity will be modulated by
pharmacologic and genetic approaches. The genetic approach will target two major epithelial NM-II isoforms,
NM-IIA and NM-IIC, by selectively downregulating their expression in human IEC using CRISPR/Cas9 gene
editing and RNA interference. In vivo NM-II functions will be examined by using mice with either intestinal
epithelial specific knockout of NM-IIA, or total knockout of NM-IIC. To determine which NM-II activity is
essential for bacterial-IEC interactions, we will utilize IEC cells and transgenic mice expressing NM-IIA mutants
deficient in either actin filament cross-linking, or filament contraction activities. Significance: the proposal will
reveal novel insights into understanding how the intestinal epithelium controls pathogenic bacterial infections
and will identify new targets for therapeutic interventions to treat diseases caused by enteric pathogens.
摘要
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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Andrei Ivanovich Ivanov其他文献
Andrei Ivanovich Ivanov的其他文献
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{{ truncateString('Andrei Ivanovich Ivanov', 18)}}的其他基金
Novel cytoskeletal mechanisms of pathogenic bacteria interactions with intestinal epithelium
病原菌与肠上皮相互作用的新细胞骨架机制
- 批准号:
10663379 - 财政年份:2022
- 资助金额:
$ 50.68万 - 项目类别:
Unconventional myosins and the regulation of gut barrier integrity and restitution during inflammation
非常规肌球蛋白以及炎症期间肠道屏障完整性和恢复的调节
- 批准号:
10443882 - 财政年份:2020
- 资助金额:
$ 50.68万 - 项目类别:
Unconventional myosins and the regulation of gut barrier integrity and restitution during inflammation
非常规肌球蛋白以及炎症期间肠道屏障完整性和恢复的调节
- 批准号:
10261489 - 财政年份:2020
- 资助金额:
$ 50.68万 - 项目类别:
Unconventional myosins and the regulation of gut barrier integrity and restitution during inflammation
非常规肌球蛋白以及炎症期间肠道屏障完整性和恢复的调节
- 批准号:
10094455 - 财政年份:2020
- 资助金额:
$ 50.68万 - 项目类别:
Actomyosin cytoskeleton and the regulation of intestinal eipithelial barrier
肌动球蛋白细胞骨架与肠上皮屏障的调节
- 批准号:
9304208 - 财政年份:2016
- 资助金额:
$ 50.68万 - 项目类别:
Actomyosin cytoskeleton and the regulation of intestinal eipithelial barrier
肌动球蛋白细胞骨架与肠上皮屏障的调节
- 批准号:
9606158 - 财政年份:2016
- 资助金额:
$ 50.68万 - 项目类别:
Junctional exocytosis and breakdown of the intestinal barrier in inflammation
炎症中的连接胞吐作用和肠道屏障的破坏
- 批准号:
8465630 - 财政年份:2010
- 资助金额:
$ 50.68万 - 项目类别:
Junctional exocytosis and breakdown of the intestinal barrier in inflammation
炎症中的连接胞吐作用和肠道屏障的破坏
- 批准号:
8051683 - 财政年份:2010
- 资助金额:
$ 50.68万 - 项目类别:
Actin dynamics and regulation of epithelial barrier in intestinal inflammation
肠道炎症中肌动蛋白动力学和上皮屏障的调节
- 批准号:
8587379 - 财政年份:2010
- 资助金额:
$ 50.68万 - 项目类别:
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