Molecular Mechanisms of Epithelial Contribution to Esophageal Inflammation and Tissue Repair
上皮细胞对食管炎症和组织修复贡献的分子机制
基本信息
- 批准号:10359705
- 负责人:
- 金额:$ 35.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAnimal Disease ModelsBarrett EsophagusBenignBiological AssayBiological ProcessBiologyBlood VesselsCXCL9 geneCancer EtiologyCell CommunicationCell ProliferationCell SurvivalCellsCessation of lifeChIP-seqComplementComplexDataDevelopmentDiagnosisDiseaseDysplasiaEndothelial CellsEnvironmentEpithelialEpithelial CellsEquilibriumEsophageal AdenocarcinomaEsophageal DiseasesEsophageal Intraepithelial NeoplasiaEsophageal Squamous CellEsophagitisEsophagusGastroenterologyGastroesophageal reflux diseaseGastrointestinal tract structureGoalsGranulocyte-Macrophage Colony-Stimulating FactorGrowthHomeostasisI Kappa B-AlphaImmuneImmunityIn VitroInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjuryKnowledgeLeadLigandsMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of esophagusModelingMolecularMusNF-kappaB-inducing kinaseNitroquinolinesNuclearOrganoidsOxidesPathogenesisPathway interactionsPatientsPhenotypePlayPrevalenceProcessProductionPublicationsRegulationResearchResearch PersonnelResourcesRoleSignal TransductionSkinSquamous CellStat3 proteinStratified EpitheliumSurvival RateSystemTNF geneTestingTissuesTransgenic MiceUnited StatesVisitangiogenesiscancer cellcancer therapycell growthcell typechemokinecytokinefactor Aimprovedin vivoinsightmouse modelnew therapeutic targetnotch proteinnovelnovel strategiesrecruitrepairedresponsethree dimensional cell culturetissue injurytissue repairtumor microenvironment
项目摘要
PROJECT SUMMARY
The overarching goal of this proposal is to understand the contribution of the epithelium to esophageal
inflammation and tissue injury through mechanistic studies of the key inflammatory mediator inhibitor of nuclear
factor kappa-B kinase subunit beta (IKKβ). The significance of this proposal lies in 1) the prevalence of
esophageal disorders, which are a significant burden in the U.S. and throughout the world and 2) the central
role of epithelial IKKβ signaling in the regulation of diverse biological processes, such as inflammation,
immunity, cell survival, and cell growth in numerous tissues and cell types. The PI is an early-stage investigator
who is an expert in epithelial inflammation and injury, inflammatory mediators, animal models of disease, and
epithelial biology, and is supported by a superb research team, complemented by expert collaborators. Here,
we will take advantage of new mouse models and complementary in vitro systems utilizing 3D culture system
to test the hypothesis that activation of epithelial IKKβ signaling produces a pro-inflammatory, pro-
proliferative, pro-angiogenic milieu that tips the balance towards the development esophageal diseases such
as squamous cell dysplasia and cancer. To explore these processes, we will undertake three interrelated
Specific Aims. In Aim 1, we will determine the functional interplay of STAT3 activation and IKKβ signaling in
the proliferative response of esophageal epithelial cells. This will be undertaken using mice with both active
IKKb and STAT3 deletion, and three-dimensional (3D) mouse esophageal organoids. In Aim 2, we will define
the role of epithelial IKKβ signaling in epithelial-endothelial cell interactions during the transition from a normal
state to esophageal dysplasia. Here, we will utilize a novel transgenic mouse model with esophageal epithelial
IKKβ deletion treated with 4-Nitroquinoline 1-oxide (4-NQO), and 3D vascular network formation assay. In Aim
3, we will investigate the role of epithelial IKKβ signaling in the inflammatory response of esophageal epithelial
cells during the transition from a normal state to esophageal dysplasia. This will be undertaken new transgenic
mouse model of esophageal epithelial IKKβ deletion that is treated with 4-NQO. These complementary
approaches will confirm and extend the findings from our Preliminary Data and from our recent publication in
Gastroenterology. Moreover, the proposed research will be supported by the superb and collegial intellectual
environment and the exceptional resources and facilities available to the PI. We anticipate that these studies
will provide insight into the factors that regulate normal esophageal epithelial homeostasis, the
microenvironment, and the pathways that are disrupted in esophageal diseases, both benign and malignant.
项目摘要
这项提议的首要目标是了解上皮细胞对食管癌的作用。
炎症和组织损伤的机制研究的关键炎症介质抑制剂的核
因子κ-B激酶β亚基(IKKβ)。这一建议的意义在于:1)
食管疾病,这是美国和全世界的重大负担,和2)中央
上皮IKKβ信号在调节多种生物过程中的作用,如炎症,
免疫、细胞存活和细胞生长。PI是早期研究者
他是上皮炎症和损伤、炎症介质、疾病动物模型和
上皮生物学,并由一流的研究团队支持,并辅以专家合作者。在这里,
我们将利用新的小鼠模型和利用3D培养系统的补充体外系统,
为了验证上皮IKKβ信号的激活产生促炎性、促炎性、
增殖,促血管生成的环境,倾向于发展食管疾病,
鳞状细胞发育不良和癌症。为了探索这些过程,我们将进行三个相互关联的
具体目标。在目标1中,我们将确定STAT 3激活和IKKβ信号转导在人卵巢癌中的功能相互作用。
食管上皮细胞的增殖反应。这将使用具有两种活性的小鼠来进行。
IKKb和STAT 3缺失以及三维(3D)小鼠食管类器官。在目标2中,我们定义
上皮细胞IKKβ信号在从正常细胞转变为正常细胞过程中上皮-内皮细胞相互作用中的作用
食管发育不良。在这里,我们将利用一种新型的食管上皮转基因小鼠模型
用4-硝基喹啉1-氧化物(4-NQO)处理IKKβ缺失,和3D血管网络形成测定。在Aim中
3、我们将研究上皮IKKβ信号在食管上皮炎症反应中的作用。
细胞从正常状态过渡到食管发育不良。这将是新的转基因
用4-NQO处理的食管上皮IKKβ缺失小鼠模型。这些互补
这些方法将证实和扩展我们的初步数据和我们最近发表在《
胃肠病学。此外,拟议的研究将得到一流的和大学的知识分子的支持,
环境和特殊的资源和设施提供给PI。我们预计这些研究
将提供对调节正常食管上皮稳态的因素的深入了解,
微环境,以及良性和恶性食管疾病中被破坏的途径。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Autophagy as a cytoprotective mechanism in esophageal squamous cell carcinoma.
- DOI:10.1016/j.coph.2018.04.003
- 发表时间:2018-08
- 期刊:
- 影响因子:4
- 作者:Hall TM;Tétreault MP;Hamilton KE;Whelan KA
- 通讯作者:Whelan KA
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MARIE-PIER TETREAULT其他文献
MARIE-PIER TETREAULT的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('MARIE-PIER TETREAULT', 18)}}的其他基金
Measurement and Molecular Mechanisms of Altered Esophageal Distensibility
食管扩张性改变的测量和分子机制
- 批准号:
10439751 - 财政年份:2018
- 资助金额:
$ 35.55万 - 项目类别:
Measurement and Molecular Mechanisms of Altered Esophageal Distensibility
食管扩张性改变的测量和分子机制
- 批准号:
10200795 - 财政年份:2018
- 资助金额:
$ 35.55万 - 项目类别:
The role of microenvironment in esophageal epithelial homeostasis
微环境在食管上皮稳态中的作用
- 批准号:
9324965 - 财政年份:2015
- 资助金额:
$ 35.55万 - 项目类别:
The role of microenvironment in esophageal epithelial homeostasis
微环境在食管上皮稳态中的作用
- 批准号:
8441893 - 财政年份:2013
- 资助金额:
$ 35.55万 - 项目类别:
The role of microenvironment in esophageal epithelial homeostasis
微环境在食管上皮稳态中的作用
- 批准号:
8678907 - 财政年份:2013
- 资助金额:
$ 35.55万 - 项目类别:
相似海外基金
Investigating how TRAF1 Controls Inflammasome Activation in Animal Disease Models of Inflammatory Arthritis and Peritonitis
研究 TRAF1 如何控制炎症性关节炎和腹膜炎动物疾病模型中的炎症小体激活
- 批准号:
449429 - 财政年份:2020
- 资助金额:
$ 35.55万 - 项目类别:
Studentship Programs
Establishment of animal disease models for intractable pediatric diseases due to defects of RNA metabolism and development of new therapeutics
RNA代谢缺陷引起的儿科疑难疾病动物模型的建立及新疗法的开发
- 批准号:
20H03644 - 财政年份:2020
- 资助金额:
$ 35.55万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Functional analysis of type 2 diabetes susceptibility genes using animal disease models
利用动物疾病模型对2型糖尿病易感基因进行功能分析
- 批准号:
18K08466 - 财政年份:2018
- 资助金额:
$ 35.55万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Cell therapy of adipocytes derived from human iPS cells using cellcontainers and animal disease models
使用细胞容器和动物疾病模型对源自人类 iPS 细胞的脂肪细胞进行细胞治疗
- 批准号:
24659444 - 财政年份:2012
- 资助金额:
$ 35.55万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Analysis of genes involved in the pathogenesis of the arthritis using animal disease models..
使用动物疾病模型分析涉及关节炎发病机制的基因。
- 批准号:
17500284 - 财政年份:2005
- 资助金额:
$ 35.55万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
ESTABLISHMENT OF THE DEVELOPING AND SUPPLING SYSTEMS FOR NEW ANIMAL,DISEASE MODELS FROM SUBSPECIES OF THE MOUSE
小鼠亚种新动物、疾病模型的开发和供应体系的建立
- 批准号:
07556128 - 财政年份:1995
- 资助金额:
$ 35.55万 - 项目类别:
Grant-in-Aid for Scientific Research (A)














{{item.name}}会员




