The role of microenvironment in esophageal epithelial homeostasis

描述（由申请人提供）：本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计划，旨在发展胃肠病学的学术基础科学研究事业。PI已经完成了她的博士学位，在细胞生物学和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研究领域，需要额外的必要的多学科培训。PI将获得独特的技能集来研究关键炎症介质IKK¿在食管微环境调节中的作用。虽然细胞因子、趋化因子和炎症介质的激活已经在食道疾病中被确定，但关于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，整合免疫学和肿瘤微环境的概念。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。候选人的共同导师Anil Rustgi博士和Sandra Ryeom博士在转录调控、信号转导、三维培养、血管生成和微环境调控方面提供额外的专业知识。一个由美国国立卫生研究院资助的具有广泛专业知识的主要调查人员组成的极好的咨询委员会已经成立，以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培养系统的互补体外系统来验证食道上皮细胞内IKK¿通路的激活产生微环境的假设，该微环境可增强食道发育不良、癌症和其他疾病。为了探索这些过程，我们将进行三个相互关联的具体目标。在Aim 1 （K99期）中，我们将定义上皮IKK¿信号在食管微环境和上皮-内皮细胞相互作用中的作用。这将采用一种新的转基因小鼠模型和原代食管上皮细胞在三维组织背景下进行。在Aim 2 （K99/R00期）中，我们将确定上皮IKK¿信号在限制食管间质肌成纤维细胞扩张中的需求。在这里，我们将使用食管特异性IKK¿敲除小鼠和3D培养。在Aim 3 （R00期）中，我们将确定STAT3激活和IKK¿/NF¿B信号在食管上皮细胞炎症反应中的功能相互作用。为了检验这些相互作用，我们将使用IKK敲入小鼠与STAT3粘接小鼠杂交。建议的研究将会得到学院一流的学术环境，以及PI所拥有的特殊资源和设施的支持。我们预计这些研究将提供对调节正常食管上皮稳态的因素、微环境和食管疾病（包括良性和恶性）中被破坏的途径的见解。

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.