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指导培训计划，随后是一个为期三年的独立培训计划。 PI 拥有胃肠病学学术基础科学研究职业发展计划。完成了细胞生物学博士学位，并寻求利用现有的研究经验和技能成为需要额外基本多方面研究领域的成功独立调查员 PI 将获得独特的技能来研究关键炎症介质的作用。 IKKβ 调节食管微环境，同时激活细胞因子、趋化因子和食管疾病中已发现炎症介质，但有关其的信息很少为了剖析这些疾病中这种激活的分子机制，PI 将剖析相关途径。通过正式课程整合免疫学和肿瘤微环境的概念，掌握相关技术技能以及这些领域专家的指导。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。候选人的共同导师 Anil Rustgi 博士和 Sandra Ryeom 博士提供了转录方面的额外专业知识调节、信号转导、三维培养、血管生成和调节一个由 NIH 资助的具有广泛领域的领先研究人员组成的卓越咨询委员会。在这里，我们将利用已经形成的专业知识来提供科学和专业的指导。新的小鼠模型和互补的体外系统利用 3D 培养系统来检验以下假设：食管上皮细胞内 IKKβ 通路的激活产生了一个微环境，可增强为了探索这些过程，我们将进行三项研究。在目标 1（K99 阶段）中，我们将定义上皮 IKKβ 信号传导在这将使用食道中的微环境和上皮内皮细胞相互作用进行。目标 2 中的新型转基因小鼠模型和 3D 组织环境中的原代食管上皮细胞。（K99/R00 阶段），我们将确定上皮 IKKβ 信号传导在限制扩张中的要求在这里，我们将利用食管特异性 IKKβ 敲除小鼠和 3D。在目标 3（R00 阶段）中，我们将确定 STAT3 激活和 IKKβ/NFκB 的功能相互作用。为了检查这些相互作用，我们将研究食管上皮细胞炎症反应中的信号传导。使用与 STAT3 floxed 小鼠杂交的 IKKβ 敲入小鼠。拟议的研究将得到支持。凭借一流的学院式智力环境以及卓越的资源和设施我们预计这些研究将深入了解调节正常食管的因素上皮稳态、微环境以及食管疾病中被破坏的途径，分为良性和恶性。