The role of microenvironment in esophageal epithelial homeostasis
The role of microenvironment in esophageal epithelial homeostasis
批准号:
9324965
负责人:
MARIE-PIER TETREAULT
金额:
$23.89万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-08-06 至 2018-07-31
关键词:
Advisory CommitteesAreaBarrett EsophagusBasic ScienceBenignCell CommunicationCellsCellular biologyComplexCytokine ActivationDevelopmentDiagnosisDimensionsDiseaseDisease modelDoctor of PhilosophyEndothelial CellsEnvironmentEpithelialEpithelial CellsEpithelial-Stromal CommunicationEpitheliumEquilibriumEsophagealEsophageal AdenocarcinomaEsophageal DiseasesEsophageal Intraepithelial NeoplasiaEsophageal Squamous CellEsophagitisEsophagusFibroblastsFosteringFundingGastroenterologyGenetically Engineered MouseGrowthHomeostasisImmuneImmunologyIn VitroInflammationInflammation MediatorsInflammatoryInflammatory ResponseInvestigationKnock-in MouseKnockout MiceKnowledgeLeadLoxP-flanked alleleMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of esophagusMediatingMentorsMentorshipMolecularMusMyofibroblastPathway interactionsPhasePhenotypePlayPrecancerous ConditionsProcessProductionProgram DevelopmentRegulationResearchResearch PersonnelResourcesRoleSTAT3 geneSignal PathwaySignal TransductionSystemTechnical ExpertiseTechniquesTestingTissuesTrainingTraining ProgramsTranscriptional RegulationTransgenic MiceUnited StatesUnited States National Institutes of HealthVascular Endothelial Growth FactorsWorkangiogenesiscancer cellcancer preventioncancer therapycareerchemokinecytokineexperiencein vivoinsightmouse modelnovelnovel strategiesskillsthree dimensional cell culturetumortumor microenvironment
中文摘要
抽象/项目总结
英文摘要
Abstract/Project Summary
This proposal describes a two year integrated mentored training program followed by a three year independent
program for the development of an academic basic science research career in gastroenterology. The PI has
completed her Ph.D. in Cell Biology and seeks to build on her existing research experience and skills to
become a successful independent investigator in an area of research that requires additional essential multi
disciplinary training. The PI will acquire unique skills set to study the role of the key inflammatory mediator
IKKβ in the regulation of the esophageal microenvironment. While activation of cytokines, chemokines, and
inflammatory mediators has been identified in esophageal diseases, little information is available about the
molecular mechanisms of this activation in these diseases. To dissect the relevant pathways, the PI will
integrate concepts from immunology and the tumor microenvironment through formal coursework, mastering of
relevant technical skills, and mentorship by experts in these fields. The candidate’s Mentor, Dr. Jonathan Katz,
is an expert in geneticallyengineered mouse models of disease and esophageal squamous cell biology. The
candidate’s CoMentors, Dr. Anil Rustgi and Dr. Sandra Ryeom, provide additional expertise in transcriptional
regulation, signal transduction, threedimensional culture, angiogenesis, and the regulation of the
microenvironment. A superb advisory committee composed of leading NIHfunded investigators with broad
expertise has been formed to provide scientific and professional guidance. 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 the IKKβ pathway within esophageal epithelial cells produces a microenvironment that potentiates
esophageal dysplasia, cancer, and other diseases. To explore these processes, we will undertake three
interrelated Specific Aims. In Aim 1 (K99 phase), we will define the role of epithelial IKKβ signaling in the
microenvironment and in epithelialendothelial cell interactions in the esophagus. This will be undertaken using
a novel transgenic mouse model and primary esophageal epithelial cells in a 3D tissue context. In Aim 2
(K99/R00 phases), we will determine the requirement for epithelial IKKβ signaling in limiting expansion of
esophageal stromal myofibroblasts. Here, we will utilize esophagealspecific IKKβ knockout mice and 3D
culture. In Aim 3 (R00 phase), we will determine the functional interplay of STAT3 activation and IKKβ/NFκB
signaling in the inflammatory response of esophageal epithelial cells. To examine these interactions, we will
employ IKKβ knockin mice that are crossed with STAT3 floxed mice. The proposed research will be supported
by the superb and collegial intellectual environment as well as 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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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