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
摘要/项目摘要:
--
这份建议书描述了先是两年的综合导师培训计划,然后是三年的独立培训计划。
该计划旨在促进中国胃肠病学专业的学术、基础科学、研究和职业发展。
完成了她在细胞和生物学领域的博士学位,并寻求在她现有的生物研究经验和技能的基础上进一步发展。
成为一名成功的、独立的调查人员,在一个需要额外的、必不可少的和多方面的研究领域,成为一名独立的调查人员。
纪律和培训。他将获得独特的调解技能,并将致力于学习这位最关键的炎症性媒体调解人的主要角色。
IKKβ参与了对食道微环境的最新调节,同时还激活了多种细胞因子、趋化因子、细胞因子和细胞因子。
目前还没有发现炎性介质在食道疾病中的存在,但目前关于这些疾病的信息很少。
在这些疾病中,这种激活的分子机制是可能的。为了进一步剖析这些相关的信号通路,我们将对其进行研究。
通过正规的教学课程,整合免疫学和肿瘤微环境的概念,掌握免疫学的基本原理。
这些领域的专家提供了相关的技术技能、技能和导师指导。这位候选人的导师Jonathan博士和Katz博士说。
他是基因工程动物模型和食道鳞状上皮细胞生物学领域的资深专家。
候选人的合作导师,包括Anil博士和Rustgi博士,以及Sandra博士和Ryeom博士,将为他们在转录方面提供更多的医学专业知识。
调控、信号转导、三维细胞培养、血管生成等是细胞的主要调控手段。
微环境。一个由美国国立卫生研究院资助的全球主要调查人员组成的卓越的全球顾问委员会,具有广泛的影响力。
我们还没有形成专门的专业知识,以便提供更科学的指导和更专业的指导。在这里,我们将充分利用这一优势。
新的小鼠模型在体外培养系统中建立和补充细胞,利用3D细胞培养系统来进一步检验这一假说。
食道上皮细胞内Kikkβ信号通路的激活会产生一种新的微环境,这种微环境会增强食道上皮细胞的功能。
食道不典型增生、食道癌、食管炎等常见疾病。为了更好地探索这些新的过程,我们将分别进行以下三个方面的工作。
相互关联的具体目标。在目标1阶段(K99阶段)中,我们将不会定义上皮样细胞β信号在未来阶段的重要作用。
微环境在上皮细胞和内皮细胞之间的相互作用发生在新的食道中。因此,这项研究将不再使用。
在一个全新的3D组织环境中,一种全新的转基因小鼠食道上皮细胞模型和原代食道上皮细胞被发现。
(K99/R00阶段),我们将不会确定在限制β的扩张率方面对上皮样细胞的要求。
食道间质和肌成纤维细胞。在这里,我们将继续利用食道特异的β基因敲除小鼠和3D。
文化。在目标3阶段(R00阶段),我们将无法确定3激活过程和Kikk STAT3/NFκB的功能和相互作用机制。
信号转导参与了食道上皮细胞的炎症反应。为了更好地审视这些相互作用,我们将:
使用Kikkβ来敲入那些已经与TSTAT3杂交的小鼠。我们将不会支持这项新的研究计划。
通过提供一流的环境和良好的大学教育知识环境,以及一流的教育资源和可用的教育设施。
我们预计,这些研究将为我们提供对调节正常食道功能的主要因素的更深入的了解。
上皮细胞的动态平衡,以及微环境,控制着在食道和食道疾病中被破坏的主要途径。
既有良性的,也有恶性的。
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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