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The role of microenvironment in esophageal epithelial homeostasis

微环境在食管上皮稳态中的作用

基本信息

批准号：
9324965
负责人：
MARIE-PIER TETREAULT
金额：
$ 23.89万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-06 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324965
关键词：
Advisory Committees Area Barrett Esophagus Basic Science Benign Cell Communication Cells Cellular biology Complex Cytokine Activation Development Diagnosis Dimensions Disease Disease model Doctor of Philosophy Endothelial Cells Environment Epithelial Epithelial Cells Epithelial-Stromal Communication Epithelium Equilibrium Esophageal Esophageal Adenocarcinoma Esophageal Diseases Esophageal Intraepithelial Neoplasia Esophageal Squamous Cell Esophagitis Esophagus Fibroblasts Fostering Funding Gastroenterology Genetically Engineered Mouse Growth Homeostasis Immune Immunology In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Investigation Knock-in Mouse Knockout Mice Knowledge Lead LoxP-flanked allele Malignant - descriptor Malignant Neoplasms Malignant neoplasm of esophagus Mediating Mentors Mentorship Molecular Mus Myofibroblast Pathway interactions Phase Phenotype Play Precancerous Conditions Process Production Program Development Regulation Research Research Personnel Resources Role STAT3 gene Signal Pathway Signal Transduction System Technical Expertise Techniques Testing Tissues Training Training Programs Transcriptional Regulation Transgenic Mice United States United States National Institutes of Health Vascular Endothelial Growth Factors Work angiogenesis cancer cell cancer prevention cancer therapy career chemokine cytokine experience in vivo insight mouse model novel novel strategies skills three dimensional cell culture tumor tumor microenvironment

项目摘要

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.

摘要/项目摘要该提案描述了一个为期两年的综合辅导培训计划，然后是一个为期三年的独立培训计划。计划的学术基础科学研究事业的发展在胃肠病学。PI有完成了她的博士学位在细胞生物学，并寻求建立在她现有的研究经验和技能，成为一个成功的独立调查员在一个研究领域，需要额外的基本多学科学科培训。PI将获得独特的技能，以研究关键炎症介质的作用。 IKKβ在食管微环境调节中的作用。炎症介质已被确定在食管疾病，很少有信息是关于这些疾病中这种激活的分子机制。为了剖析相关的通路，PI将通过正式的课程整合免疫学和肿瘤微环境的概念，掌握相关的技术技能，并由这些领域的专家指导。候选人的导师，乔纳森卡茨博士，是基因工程小鼠疾病模型和食管鳞状细胞生物学方面的专家。候选人的导师Anil Rustgi博士和Sandra Ryeom博士提供了转录方面的额外专业知识调控，信号转导，三维培养，血管生成，以及微环境一个由美国国立卫生研究院资助的主要研究人员组成的一流咨询委员会，形成了专门知识，提供科学和专业指导。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，以测试以下假设：食管上皮细胞内IKKβ通路的激活产生了一种微环境，食管发育不良，癌症和其他疾病。为了探索这些过程，我们将进行三个相关的具体目标。在目标1（K99期），我们将确定上皮IKKβ信号转导在细胞凋亡中的作用。微环境和食管上皮细胞与内皮细胞的相互作用。这将采用一种新的转基因小鼠模型和3D组织背景下的原代食管上皮细胞。 (K99/R 00期），我们将确定上皮IKKβ信号传导在限制细胞增殖中的需要。食管基质肌成纤维细胞。在这里，我们将利用食管癌特异性IKKβ基因敲除小鼠和3D 在Aim 3（R 00期），我们将确定STAT 3激活和IKKβ/NFκB的功能相互作用食管上皮细胞炎症反应中的信号传导。为了研究这些相互作用，我们将利用IKKβ基因敲除小鼠与STAT 3基因敲除小鼠杂交，该研究将得到支持一流的学术环境以及卓越的资源和设施，我们预计这些研究将提供对调节正常食管癌的因素的深入了解。上皮内稳态、微环境和食管疾病中被破坏的途径，良性和恶性都有。