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：
8678907
负责人：
MARIE-PIER TETREAULT
金额：
$ 9万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8678907
关键词：
Advisory Committees Area Barrett Esophagus Basic Science Benign Cell Communication Cells Cellular biology Complex Cytokine Activation Development Diagnosis Disease 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 Malignant - descriptor Malignant Neoplasms Malignant neoplasm of esophagus Mediating Mentors Mentorship Molecular Mus Myofibroblast Pathway interactions Phase Play Precancerous Conditions Process Production Program Development Regulation Research Research Personnel Resources Role STAT3 gene Signal Pathway Signal Transduction System 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 public health relevance skills tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): 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 he key inflammatory mediator IKK¿ 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 genetically-engineered mouse models of disease and esophageal squamous cell biology. The candidate's Co-Mentors, Dr. Anil Rustgi and Dr. Sandra Ryeom, provide additional expertise in transcriptional regulation, signal transduction, three-dimensional culture, angiogenesis, and the regulation of the microenvironment. A superb advisory committee composed of leading NIH-funded 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 IKK¿ 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 IKK¿ signaling in the microenvironment and in epithelial-endothelial cell interactions i 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 IKK¿ signaling in limiting expansion of esophageal stromal myofibroblasts. Here, we will utilize esophageal-specific IKK¿ knockout mice and 3D culture. In Aim 3 (R00 phase), we will determine the functional interplay of STAT3 activation and IKK¿/NF¿B signaling in the inflammatory response of esophageal epithelial cells. To examine these interactions, we will employ IKK¿ knock-in 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.

描述（由申请人提供）：该提案描述了为期两年的综合指导培训计划，以及随后为期三年的独立计划，以发展胃肠病学的学术基础科学研究职业。寻求利用现有的研究经验和技能，成为需要额外必要的多学科培训的研究领域的一名成功的独立研究者。PI 将获得独特的技能来研究关键炎症介质 IKK 的作用。虽然食管疾病中存在细胞因子、趋化因子和炎症介质的激活，但有关这些疾病中这种激活的分子机制的信息很少，为了剖析相关途径，PI 将进行整合。通过正式课程、掌握相关技术技能以及这些领域专家的指导，候选人的导师 Jonathan Katz 博士是免疫学和肿瘤微环境的专家。候选人的联合导师 Anil Rustgi 博士和 Sandra Ryeom 博士在转录调控、信号遗传转导、三维培养、血管生成和调控方面提供了额外的专业知识。我们已经成立了一个由 NIH 资助的具有广泛专业知识的领先研究人员组成的卓越咨询委员会，以提供科学和专业的指导。在这里，我们将利用新的小鼠模型和互补的体外利用系统。 3D 培养系统测试 IKK 激活的假设食管上皮细胞内的通路产生了一个促进食管发育不良、癌症和其他疾病的微环境。为了探索这些过程，我们将采取三个相互关联的具体目标，在目标 1（K99 阶段）中，我们将定义上皮 IKK 的作用。在目标 2（K99/R00 阶段）中，我们将使用新型转基因小鼠模型和原代食管上皮细胞来研究微环境中的信号传导以及食管中的上皮内皮细胞相互作用。上皮 IKK 的要求¿限制食管基质肌成纤维细胞扩张的信号传导在这里，我们将利用食管特异性 IKK¿在 Aim 3（R00 期）中，我们将确定 STAT3 激活和 IKK 的功能相互作用。 /NF??食管上皮细胞炎症反应中的 B 信号传导为了检查这些相互作用，我们将使用 IKK¿拟议的研究敲入小鼠与 STAT3 floxed 小鼠杂交。拟议的研究将得到一流的学院智力环境以及 PI 可用的特殊资源和设施的支持，我们预计这些研究将提供深入的了解。调节正常食管上皮稳态的因素、微环境以及食管良性和恶性疾病中被破坏的途径。