The Role of STAT2 in Flat Non-Polypoid Colorectal Neoplasia
STAT2 在扁平非息肉样结直肠肿瘤中的作用
基本信息
- 批准号:9305364
- 负责人:
- 金额:$ 7.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenomatous PolypsAlpha CellAnatomyAnimal ModelAnimalsApplications GrantsAzoxymethaneBiological AssayCDX2 geneCarcinomaChemical ModelsCo-ImmunoprecipitationsColitisColonColon CarcinomaColonic NeoplasmsColonoscopyColorectalColorectal AdenocarcinomaColorectal AdenomaColorectal CancerColorectal NeoplasmsCrohn&aposs diseaseDecision MakingDevelopmentDiseaseEpithelial CellsEpitheliumEventFrequenciesGeneticGenotypeHumanIncidenceInflammationInflammatoryInflammatory Bowel DiseasesIntestinesInvadedKnockout MiceKnowledgeLesionLightLoxP-flanked alleleMalignant NeoplasmsModelingMolecularMonitorMorphologyMusOncogenicPathway interactionsPatientsPeriodicityPlayPolypoid LesionPositioning AttributeProcessPropertyProteinsRiskRisk FactorsRoleSTAT2 geneSeveritiesSignal TransductionSodium Dextran SulfateTP53 geneTestingTherapeutic InterventionTimeTumor Cell LineTumor MarkersTumorigenicityUlcerative ColitisUnited StatesWild Type Mouseadenomaattenuationcancer cellcancer preventioncolitis associated cancercolon carcinogenesiscombinatorialhigh riskillness lengthinflammatory markerinsightknock-downmetaplastic cell transformationmouse modelnew therapeutic targetpredictive toolsresponsesextranscription factortumortumorigenic
项目摘要
Summary
Non-polypoid (flat) colorectal neoplasms account for as many as two-thirds of all colorectal lesions
in patients with inflammatory bowel disease (IBD), a high risk factor for the development of
colorectal cancer (CRC), namely, colitis-associated colon cancer (CAC). Flat lesions are five
times more likely than polypoid lesions to progress to invasive colorectal adenocarcinoma, in part
because they are more difficult to detect and completely remove. Thus, identifying the molecular
pathways responsible for determining whether tumors become flat or polypoid may provide
valuable insight into cancer prevention and/or treatment. Previous studies suggest that the timing
of p53 alterations in colorectal cancer development determine whether the tumors are flat or
polypoid, and our recent studies suggest that the transcription factor STAT2 may be an essential
molecule in the development of flat colorectal adenomas. Thus, we propose to test the
hypothesis that STAT2 contributes to the preferential development of flat non-polypoid as
opposed to polypoid colorectal tumors following p53 inactivation. We plan to address this
by performing the following central aim: Determine the role of STAT2 in the development of flat
non-polypoid colorectal tumors in the setting of p53 inactivation to address two important
questions: 1) does colonic epithelial cell intrinsic STAT2 signaling play a role in the formation of
flat non-polypoid tumors?, and 2) does STAT2 activate and sustain a pro-inflammatory
microenvironment conducive to the preferential development of flat non-polypoid colorectal
tumors when p53 is inactivated in the colonic epithelium? To investigate the effect of STAT2 in
the development of flat non-polypoid lesions, we will employ the well-established dextran sulfate
sodium (DSS)-induced colitis model using conditional p53 and Stat2 knockout mice and
conventional Stat2 knockout mice. With this model, we are in a unique position to monitor disease
development and progression.
Significance: Our findings will provide crucial information on the initial cellular transformation
events that give rise to flat non-polypoid colorectal tumors, which are more likely to become
cancer under conditions of p53 inactivation; a major gap in knowledge to which we still understand
very little. Hence defining the role of STAT2 in the development of flat colonic tumors is key in the
identification of tumor biomarkers as predictive tools for cancer prevention and development of
novel targeted therapies.
总结
非息肉样(扁平)结直肠肿瘤占所有结直肠病变的三分之二
在患有炎症性肠病(IBD)的患者中,
结直肠癌(CRC),即结肠炎相关结肠癌(CAC)。扁平病变有5个
比息肉样病变进展为浸润性结直肠腺癌的可能性高一倍,部分
因为它们更难以检测和完全去除。因此,识别分子
负责决定肿瘤是扁平还是息肉样的通路可能提供
对癌症预防和/或治疗有价值的见解。先前的研究表明,
p53基因在结直肠癌发展中的改变决定了肿瘤是扁平的,
我们最近的研究表明,转录因子STAT2可能是一个重要的,
分子在扁平结直肠腺瘤的发展中的作用。因此,我们建议测试
假设STAT2有助于扁平非息肉样的优先发展,
与p53失活后的息肉样结直肠肿瘤相反。我们计划解决这个问题
通过执行以下中心目标:确定STAT2在扁平细胞发育中的作用,
非息肉样结直肠肿瘤在p53失活的背景下,以解决两个重要的
问题:1)结肠上皮细胞内在的STAT2信号传导是否在结肠癌的形成中发挥作用?
扁平非息肉样肿瘤?和2)STAT2是否激活并维持促炎性细胞因子,
有利于扁平非息肉样结直肠优先发育的微环境
当p53在结肠上皮中失活时,肿瘤会发生吗?为了研究STAT2在细胞凋亡中的作用,
平坦的非息肉样病变的发展,我们将采用公认的硫酸葡聚糖
使用条件性p53和Stat2敲除小鼠的钠(DSS)诱导的结肠炎模型,
常规Stat2敲除小鼠。有了这个模型,我们在监测疾病方面处于独特的地位,
发展和进步。
意义:我们的发现将为最初的细胞转化提供关键信息。
导致扁平非息肉状结直肠肿瘤的事件,这些肿瘤更有可能成为
p53失活条件下的癌症;我们仍然了解的知识的主要差距
很少。因此,确定STAT2在扁平结肠肿瘤发展中的作用是研究STAT2在结肠癌中的作用的关键。
鉴定肿瘤生物标志物作为癌症预防和发展的预测工具
新型靶向治疗。
项目成果
期刊论文数量(0)
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ANA M GAMERO其他文献
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{{ truncateString('ANA M GAMERO', 18)}}的其他基金
Investigation of STAT2 Signaling in the tumor microenvironment
肿瘤微环境中 STAT2 信号传导的研究
- 批准号:
10661993 - 财政年份:2023
- 资助金额:
$ 7.8万 - 项目类别:
STAT2 Signaling in the Pathogenesis of Psoriasis
银屑病发病机制中的 STAT2 信号转导
- 批准号:
10418798 - 财政年份:2021
- 资助金额:
$ 7.8万 - 项目类别:
STAT2 Signaling in the Pathogenesis of Psoriasis
银屑病发病机制中的 STAT2 信号转导
- 批准号:
10303865 - 财政年份:2021
- 资助金额:
$ 7.8万 - 项目类别:
Evaluation of STAT2 in a Model of Sporadic Colorectal Cancer
散发性结直肠癌模型中 STAT2 的评估
- 批准号:
8322638 - 财政年份:2011
- 资助金额:
$ 7.8万 - 项目类别:
Evaluation of STAT2 in a Model of Sporadic Colorectal Cancer
散发性结直肠癌模型中 STAT2 的评估
- 批准号:
8203847 - 财政年份:2011
- 资助金额:
$ 7.8万 - 项目类别:
Crosstalk between STAT2 and Bim in type I IFN Signaling
I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰
- 批准号:
8253486 - 财政年份:2009
- 资助金额:
$ 7.8万 - 项目类别:
Crosstalk between STAT2 and Bim in type I IFN Signaling
I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰
- 批准号:
7697791 - 财政年份:2009
- 资助金额:
$ 7.8万 - 项目类别:
Crosstalk between STAT2 and Bim in type I IFN Signaling
I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰
- 批准号:
8073617 - 财政年份:2009
- 资助金额:
$ 7.8万 - 项目类别:
Crosstalk between STAT2 and Bim in type I IFN Signaling
I 型 IFN 信号传导中 STAT2 和 Bim 之间的串扰
- 批准号:
8464654 - 财政年份:2009
- 资助金额:
$ 7.8万 - 项目类别:
A Critical Role for Stat2 in Type 1 Intferon-Induced Apoptosis
Stat2 在 1 型干扰素诱导的细胞凋亡中的关键作用
- 批准号:
7690895 - 财政年份:2008
- 资助金额:
$ 7.8万 - 项目类别:
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