Drivers of gastric pre-neoplasia
胃肿瘤前期的驱动因素
基本信息
- 批准号:10433933
- 负责人:
- 金额:$ 39.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-10 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenocarcinomaAllelesAutomobile DrivingBiologyCancer EtiologyCancerousCell LineageCellsCessation of lifeChief CellColon CarcinomaDevelopmentDoxycyclineDysplasiaEventEvolutionFamilyGastric AdenocarcinomaGastric MetaplasiaGenesGenetic TranscriptionGlandGoalsHistologicHumanIn VitroIndividualIntestinesIntrinsic factorInvestigationKRAS oncogenesisKineticsKnowledgeLeadMaintenanceMalignant NeoplasmsMalignant neoplasm of gastrointestinal tractMalignant neoplasm of pancreasMetaplasiaMolecularMusOncogenicOutcomes ResearchPatientsProcessRNARoleSignal PathwayStomachTetanus Helper PeptideTherapeutic InterventionTimeTissuesTranscriptional RegulationTransgenic MiceUp-RegulationZymogen Granulesbasecarcinogenesiscarcinogenicitydesigndriving forcegastric carcinogenesisgastric pre-neoplasiagenomic locusin vivoinsightmalignant stomach neoplasmmouse modelnew therapeutic targetnoveloverexpressionpre-clinicalpremalignantpreventive interventiontranscription factortransdifferentiation
项目摘要
PROJECT SUMMARY / ABSTRACT
Gastric cancer is one of the most common causes of cancer-related death worldwide. It develops in a
sequential progression of a carcinogenic cascade from pre-cancerous metaplasia to cancerous dysplasia and
adenocarcinoma. However, oncogenic drivers or master regulators which lead to carcinogenic transition
between pre-cancerous and cancerous stages are uncertain. Previous investigations have noted that Kras
activity is observed in up to 40% of patients with gastric cancer and have suggested that Ras activation in
gastric cancer may promote the progression of metaplasia toward dysplasia and cancer. Our previous results
described that Kras activation in chief cells can rapidly develop metaplasia and invasive metaplasia with
dysplastic glands. These studies therefore imply that Kras activation might be a driving factor of gastric
carcinogenesis and chief cells might be an origin of gastric cancer. However, there is a clear knowledge gap
as to whether Kras activation is a critical oncogenic driver which controls the carcinogenic process of dysplasia
to adenocarcinoma. Also, while roles of Sox transcription factor activation following the oncogenic Kras
activation have been well-studied in other GI tract cancers, no studies have addressed whether such activities
are important for metaplasia development or are associated with Ras activation in gastric carcinogenesis.
We have therefore hypothesized that Kras activation is a driver of gastric carcinogenesis and metaplastic
development and progression can be controlled by upregulation of Sox9 as a downstream effector of Kras
signaling pathway. We propose two specific aims to elucidate a deeper understanding of cellular mechanisms
and events of gastric carcinogenesis using a novel inducible driver mouse model, which is a stomach- and
chief cell-specific driver mouse allele. First, we will define the oncogenic roles of Kras activation and the
lineage contribution of active Kras-induced cells during gastric carcinogenesis. Second, we will assess
functional roles of Sox9 transcription factor as a putative master regulator of metaplasia development and
progression. Our proposed study will not only define the cells of origin for gastric cancer, but also determine
the oncogenic potential and regulatory mechanisms of Kras activation during gastric cancer development.
Consequently, our results from this proposed study would provide insights in pre-clinical information to design
therapeutic interventions or to identify novel druggable targets by regulating transcriptional regulation of key
factors in patients with gastric cancer.
项目摘要/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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Eunyoung Choi其他文献
Eunyoung Choi的其他文献
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{{ truncateString('Eunyoung Choi', 18)}}的其他基金
Hierarchy of oncogenic gene mutations in gastric carcinogenesis
胃癌发生中致癌基因突变的层次
- 批准号:
10831328 - 财政年份:2022
- 资助金额:
$ 39.57万 - 项目类别:
Cell plasticity in the origin of gastric carcinogenesis
胃癌起源中的细胞可塑性
- 批准号:
10685511 - 财政年份:2022
- 资助金额:
$ 39.57万 - 项目类别:
Cell plasticity in the origin of gastric carcinogenesis
胃癌起源中的细胞可塑性
- 批准号:
10505616 - 财政年份:2022
- 资助金额:
$ 39.57万 - 项目类别:
Induction and Evolution of Metaplasia in the Stomach
胃化生的诱导和进化
- 批准号:
10667645 - 财政年份:2014
- 资助金额:
$ 39.57万 - 项目类别:
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