Turning on Persistence: Novel Molecular Determinants that Underpin P. gingivalis' Intracellular Survival In Epithelial Cells
开启持久性:支持牙龈卟啉单胞菌在上皮细胞内存活的新型分子决定因素
基本信息
- 批准号:10836756
- 负责人:
- 金额:$ 10.91万
- 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:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnti-Bacterial AgentsAutophagocytosisAutophagosomeBacteriaCell CommunicationCell Culture SystemCellsDataData AnalysesDegradation PathwayEnvironmentEnzymesEpithelial CellsEpitheliumEquilibriumEventGenetic TranscriptionGingivaGrantGrowthHSPB1 geneHomeostasisHost DefenseHumanIL-6 inhibitorImmune responseInfectionInflammation MediatorsInterleukin-6InterventionInvadedKnockout MiceKnowledgeLIGHT proteinLifeLightLinkMalignant NeoplasmsMediatingMediatorMembraneMethodsMicrotubule-Associated ProteinsModelingMolecularNutritionalOralOral cavityOral mucous membrane structureOrganismOxidation-ReductionOxidative Stress InductionPaperParentsPathway interactionsPeriodontal DiseasesPhenotypePhosphorylationPlayPorphyromonas gingivalisProtein DephosphorylationProtein IsoformsProtein Tyrosine PhosphataseProteinsResearchRoleSecureSeminalSignal InductionSiteStat3 proteinStressSubcellular structureSystemTestingTherapeuticTimeTissuesTranscriptional ActivationTranslatingTyrosineVacuoleWorkantimicrobialarmcancer cellcell typeglutathione peroxidasemicroorganismmouse modelmultidisciplinarynovelopportunistic pathogenoral cavity epitheliumoral microbial communitypathobiontpathogentrafficking
项目摘要
SUMMARY of The PARENT AWARD
A growing multidisciplinary evidence critically underpins that Porphyromonas gingivalis, a leading pathobiont of
the oral cavity that successfully remodels oral microbial communities to a pathophysiological state, can live in
concert with human gingival epithelial cells (GECs). Epithelial cells are emerged as an integrally important arm
of innate defenses in the oral mucosa, while recent observations suggest that these cells can be exploited as
privileged growth niches and a reservoir by P. gingivalis, which can intracellularly multiply and remain largely
unharmed in GECs. Despite, extensive systems level molecular knowledge exists on the P. gingivalis and GEC
interaction, there is considerably little known on the intracellular life of the organism in this central cell type. We
recently revealed that formation of autophagosomes is critical for the P. gingivalis’ intracellular replication and
evasion of the anti-microbial degradation pathways in the GECs. Our novel preliminary findings also support
that lipidation of LC3-C, a key molecule in the ‘selective autophagy’ pathway, which targets intracellular
pathogens is significantly modulated by P. gingivalis under the control of an anti-stress molecule, HSP27.
Further, glutathione peroxidase (GpX1), a major host redox balance enzyme and a regulator of autophagic flux
largely impacted on the global LC3 lipidation state of GECs upon infection. The inhibition of either HSP27 or
GpX1 appears to severely affect the intracellular trafficking and viability of the microorganism. The central
hypothesis is that P. gingivalis induces a distinct form of selective autophagy, which results in
protection of bacterial life and ultimately securing of P. gingivalis’ persistence in the oral mucosa. To
test this novel hypothesis, we will pursue two-pronged approach, where we propose the selective autophagy
requires tightly coordinated actions of HSP27 and GpX1 to form autophagosomes that fully function as
protected replicative niches for P. gingivalis. Aim 1 will define the selective molecular machinery that drives P.
gingivalis-containing autophagosome assembly under the control of HSP27 and the mechanisms that disrupt
autophagic flux for the evasion of cellular degradation pathways. Aim 2 will establish the role of GpX1 in
regulating the selective autophagy in infection via redox homeostasis and suppressing autophagolysosomal
machinery. Both aims will employ reductionist primary GECs culture systems to functionally dissect out the
mechanisms and phenotypically characterize the molecular events and sub-cellular components. Aim 3 will
establish the dual significance of these two components using oral epithelial-tissue-specific knockout mice
models. Thus, this proposal aims to fill a significant gap in our fundamental knowledge that is how P.
gingivalis, a facultatively intracellular pathogen, establishes a privileged cellular environment and converts
nutritionally rich epithelial cells into potentially a central reservoir for bacterial growth and persistence in the
oral mucosa. Ultimately, the knowledge gained may translate into molecular strategies that can control or
reduce the intracellular colonization and survival methods employed by this important opportunistic pathogen.
诺贝尔奖概要
越来越多的多学科证据表明,牙龈卟啉单胞菌,一种主要的致病菌,
成功地将口腔微生物群落重塑到病理生理状态的口腔可以生活在
与人类牙龈上皮细胞(GECs)一致。上皮细胞作为一个不可或缺的重要分支出现
口腔粘膜的先天防御,而最近的观察表明,这些细胞可以被利用,
牙龈卟啉单胞菌的特权生长小生境和储库,其可以在细胞内繁殖并大量保留
在GECs中毫发无伤。尽管如此,关于牙龈卟啉单胞菌和GEC存在广泛的系统水平分子知识
由于这种相互作用,对这种中央细胞类型中生物体的细胞内生活知之甚少。我们
最近发现,自噬体的形成对牙龈卟啉单胞菌的细胞内复制至关重要,
避免了GEC中的抗微生物降解途径。我们新的初步发现也支持了
LC 3-C是“选择性自噬”途径中的关键分子,
在抗应激分子HSP 27的控制下,牙龈卟啉单胞菌显著地调节病原体。
此外,谷胱甘肽过氧化物酶(GpX 1),一种主要的宿主氧化还原平衡酶和自噬通量的调节剂,
在感染后,这在很大程度上影响了GEC的整体LC 3脂化状态。抑制HSP 27或
GpX 1似乎严重影响微生物的细胞内运输和活力。中央
一种假说是牙龈卟啉单胞菌诱导一种独特形式的选择性自噬,
保护细菌生命并最终确保牙龈卟啉单胞菌在口腔粘膜中的持久性。到
为了验证这一新的假设,我们将采取双管齐下的方法,我们提出选择性自噬
需要HSP 27和GpX 1的紧密协调作用来形成自噬体,
保护牙龈卟啉单胞菌的复制小生境。目标1将定义驱动P的选择性分子机制。
在HSP 27控制下的含牙龈炎的自噬体组装以及破坏牙龈炎的机制
自噬通量用于逃避细胞降解途径。目的2将确定GpX 1在以下方面的作用:
通过氧化还原稳态调节感染中的选择性自噬和抑制自噬溶酶体
机械.这两个目标都将采用简化主义的主要GEC文化系统,从功能上剖析出
机制和表型表征的分子事件和亚细胞成分。目标3将
使用口腔上皮组织特异性基因敲除小鼠建立这两种成分的双重意义
模型因此,这一建议旨在填补我们的基本知识的一个重大空白,即如何P。
牙龈炎是一种兼性细胞内病原体,它建立了一个特殊的细胞环境,
营养丰富的上皮细胞进入潜在的中央水库细菌生长和持久性
口腔粘膜最终,获得的知识可能转化为分子策略,可以控制或
减少这种重要的机会性病原体所采用的细胞内定植和存活方法。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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OZLEM YILMAZ其他文献
OZLEM YILMAZ的其他文献
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{{ truncateString('OZLEM YILMAZ', 18)}}的其他基金
Endothelial Metabolic Autophagy Mechanism of Vascular Dementia in Periodontopathic Infection
牙周病感染血管性痴呆的内皮代谢自噬机制
- 批准号:
10288951 - 财政年份:2020
- 资助金额:
$ 10.91万 - 项目类别:
Turning on Persistence: Novel Molecular Determinants that Underpin P. gingivalis Intracellular Survival In Epithelial Cells
开启持久性:支持牙龈卟啉单胞菌在上皮细胞内存活的新型分子决定因素
- 批准号:
10677781 - 财政年份:2020
- 资助金额:
$ 10.91万 - 项目类别:
Turning on Persistence: Novel Molecular Determinants that Underpin P. gingivalis Intracellular Survival In Epithelial Cells
开启持久性:支持牙龈卟啉单胞菌在上皮细胞内存活的新型分子决定因素
- 批准号:
10260650 - 财政年份:2020
- 资助金额:
$ 10.91万 - 项目类别:
Turning on Persistence: Novel Molecular Determinants that Underpin P. gingivalis' Intracellular Survival In Epithelial Cells
开启持久性:支持牙龈卟啉单胞菌在上皮细胞内存活的新型分子决定因素
- 批准号:
10667170 - 财政年份:2020
- 资助金额:
$ 10.91万 - 项目类别:
Modulation of epithelial cell response by P. gingivalis
牙龈卟啉单胞菌对上皮细胞反应的调节
- 批准号:
7932534 - 财政年份:2009
- 资助金额:
$ 10.91万 - 项目类别:
Modulation of epithelial cell response by P. gingivalis
牙龈卟啉单胞菌对上皮细胞反应的调节
- 批准号:
7030530 - 财政年份:2006
- 资助金额:
$ 10.91万 - 项目类别:
Modulation of epithelial cell response by P. gingivalis
牙龈卟啉单胞菌对上皮细胞反应的调节
- 批准号:
7183602 - 财政年份:2006
- 资助金额:
$ 10.91万 - 项目类别:
Modulation of epithelial cell response by P. gingivalis
牙龈卟啉单胞菌对上皮细胞反应的调节
- 批准号:
7369705 - 财政年份:2006
- 资助金额:
$ 10.91万 - 项目类别:
Modulation of epithelial cell response by P. gingivalis
牙龈卟啉单胞菌对上皮细胞反应的调节
- 批准号:
8242902 - 财政年份:2006
- 资助金额:
$ 10.91万 - 项目类别:
Modulation of epithelial cell response by P. gingivalis
牙龈卟啉单胞菌对上皮细胞反应的调节
- 批准号:
8657376 - 财政年份:2006
- 资助金额:
$ 10.91万 - 项目类别:
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