Investigating gastric inflammation and preneoplastic progression driven by Helicobacter pylori infection
研究幽门螺杆菌感染驱动的胃部炎症和癌前进展
基本信息
- 批准号:10448881
- 负责人:
- 金额:$ 16.78万
- 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:2022-07-07 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Abnormal CellAllelesAtrophic GastritisBacteriaBacterial InfectionsCancer EtiologyCarcinomaCell LineCell LineageCell surfaceCellsCessation of lifeChronicColorectal CancerCytotoxinDevelopmentDiseaseDisease ProgressionDysplasiaEnvironmentGastric AcidGastric Chief CellsGastric MetaplasiaGastric Parietal CellsGastritisGene ExpressionGene Expression ProfileGenesGlandGoalsGuanosine Triphosphate PhosphohydrolasesHelicobacter InfectionsHelicobacter pyloriHumanImmuneImmune responseImmunityImmunotherapyIn Situ HybridizationIndividualInfectionInflammationInflammatoryInflammatory ResponseIntestinal MetaplasiaIntestinesKRAS2 geneLeadLightMUC4 mucinMalignant NeoplasmsMediatingMetaplasiaModelingMorphologyMucous body substanceMusMutationNormal CellOncogenicPTPRC genePathway interactionsPeptidyltransferasePhenotypePreneoplastic ChangeProliferatingProteinsResearchRoleSamplingSeriesSignal PathwaySignaling ProteinSourceSplenocyteStomachSurfaceT-LymphocyteT-Lymphocyte SubsetsTamoxifenTechniquesTestingTissuesToxinTransgenic OrganismsType IV Secretion System PathwayVariantVirulenceVirulence Factorscancer immunotherapycancer riskcell transformationcell typecongenicdisease phenotypeexperimental studygenetic approachimmunopathologyinsightmalignant stomach neoplasmmouse modelmutantnovelpolarized cellpremalignantpreventprogenitorprogramsprotein expressionrepairedsingle cell sequencingsingle-cell RNA sequencingstem cells
项目摘要
Project Summary
Many cancers are attributed to chronic inflammation, which can cause mutations and activate oncogenic signaling
pathways. An important example is gastric cancer, the fourth-leading cause of cancer death worldwide. At least 80%
of gastric cancer cases are attributed to stomach infection with the bacterium Helicobacter pylori (Hp), which causes
lifelong chronic inflammation that does not eradicate the infection. In some individuals, this inflammation can cause
gastric atrophy, metaplasia (conversion of one normal cell type to another), dysplasia (presence of abnormal
cells) and finally cancer, but the specific mechanism(s) through which Hp triggers this cascade are not well
understood. Similar preneoplastic changes are recapitulated in a mouse model through tamoxifen-induced
expression of active KRAS in the chief cells of the stomach (KRAS+ mice). I found that Hp infection of KRAS+ mice
exacerbated disease: compared to Hp-KRAS+ mice, Hp+KRAS+ mice had an altered trajectory of metaplasia and
accelerated dysplasia. Hp+KRAS+ mice also had expansion of “variant” pit cells (surface mucous cells) that
expressed metaplasia- and cancer-related genes like the mucin Muc4. In accordance with the hypothesis that Hp
causes cancer through eliciting chronic inflammation, Hp+KRAS+ mice had severe inflammation marked by a ten-
fold increase in T cells vs. Hp-KRAS+ mice. In this proposal I will investigate the mechanism(s) through which Hp
worsens disease in KRAS+ mice, with a broader goal of better understanding how Hp infection and its associated
chronic inflammation cause cancer. I hypothesize that Hp modulates the inflammatory response to prevent Hp
eradication from the stomach, and this deleterious immune response leads to metaplasia and dysplasia. In Aim 1 I
will perform targeted depletion of CD4+ and CD8α+ T cell subsets to assess whether immune perturbation impacts
metaplasia, dysplasia and Hp colonization. I will also assess whether T cells traffic to the stomach in Hp+KRAS+
mice or proliferate locally. Finally, I will test whether Hp+ human samples have increased T cells relative to Hp-
samples. In Aim 2 I will investigate candidate Hp virulence factors that modulate inflammation: the cag type IV
secretion system and two proteins that modulate T cells, the toxin VacA and the transpeptidase gGT. I will determine
whether virulence factor mutants can elicit the same inflammatory and disease progression phenotypes in KRAS+
mice as wild-type Hp does. In Aim 3 I will test whether variant pit cells arise from gastric progenitor cells, and will
assess disease phenotypes in Hp+KRAS+MUC4- mice to determine whether Muc4 expression drives pit cell
transformation. I will also perform spatial single-cell RNA sequencing in +/- Hp, +/- KRAS mice to discover whether
variant pit cells share a gene expression signature with Muc4-expressing cells in the “first gland” of the stomach, a
morphologically distinct gland that is believed to be a source of reparative cell lineages. Taken together, the results
of these studies will provide new understanding of how Hp infection and inflammation cause gastric preneoplastic
progression and may reveal new targets for gastric immunotherapy. These findings may also be applicable to other
cancers associated with bacterial infection and/or inflammation, like colorectal cancer.
项目摘要
许多癌症归因于慢性炎症,慢性炎症可引起突变并激活致癌信号
途径。一个重要的例子是胃癌,它是全世界癌症死亡的第四大原因。至少80%
的胃癌病例归因于胃感染幽门螺杆菌(Hp),
终身慢性炎症,不能根除感染。在某些个体中,这种炎症可能导致
胃萎缩、化生(一种正常细胞类型转化为另一种)、异型增生(存在异常
细胞),最后是癌症,但Hp触发这一级联反应的具体机制尚不清楚
明白在小鼠模型中,通过他莫昔芬诱导的
胃主细胞中活性KRAS的表达(KRAS+小鼠)。我发现KRAS+小鼠的Hp感染
恶化的疾病:与Hp-KRAS+小鼠相比,Hp+KRAS+小鼠具有改变的化生轨迹,
加速发育不良Hp+KRAS+小鼠也有“变体”凹坑细胞(表面粘液细胞)的扩增,
表达化生和癌症相关基因,如粘蛋白Muc 4。根据惠普的假设
通过引发慢性炎症导致癌症,Hp+KRAS+小鼠有严重的炎症,
与Hp-KRAS+小鼠相比,T细胞增加倍数。在本提案中,我将研究Hp
KRAS+小鼠的Hp感染及其相关性,
慢性炎症引起癌症。我假设Hp通过调节炎症反应来预防Hp
这种有害的免疫反应导致化生和发育不良。目标1 I
将对CD 4+和CD 8 α+ T细胞亚群进行靶向清除,以评估免疫扰动是否影响
化生、异型增生和Hp定植。我还将评估在Hp+KRAS+中T细胞是否运输到胃。
小鼠或局部增殖。最后,我将测试Hp+人类样本是否相对于Hp-
样品在目标2中,我将研究调节炎症的候选Hp毒力因子:cag IV型
分泌系统和两种调节T细胞的蛋白质,毒素VacA和转肽酶gGT。我会决定
毒力因子突变体是否可以在KRAS+中引起相同的炎症和疾病进展表型
与野生型Hp一样。在目标3中,我将测试变异的小凹细胞是否来自胃祖细胞,并将
评估Hp+KRAS+ MUC 4-小鼠的疾病表型,以确定Muc 4表达是否驱动凹坑细胞
转型我还将在+/- Hp,+/- KRAS小鼠中进行空间单细胞RNA测序,以发现是否
在胃的“第一腺”中,变异的小凹细胞与表达Muc 4的细胞共享基因表达特征,
在形态上不同的腺体,被认为是修复细胞谱系的来源。综合来看,
这些研究将为Hp感染和炎症是如何引起胃癌前病变提供新的认识
进展,并可能揭示胃免疫治疗的新靶点。这些发现也可能适用于其他
与细菌感染和/或炎症相关的癌症,如结肠直肠癌。
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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Valerie Phoebe O'Brien其他文献
Valerie Phoebe O'Brien的其他文献
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{{ truncateString('Valerie Phoebe O'Brien', 18)}}的其他基金
Investigating gastric inflammation and preneoplastic progression driven by Helicobacter pylori infection
研究幽门螺杆菌感染驱动的胃部炎症和癌前进展
- 批准号:
10661588 - 财政年份:2022
- 资助金额:
$ 16.78万 - 项目类别:
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