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，然后是一个为期三年的独立计划，用于发展胃肠病学的学术基础科学研究事业。PI已完成博士学位。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，需要额外的必要的多学科培训。PI将获得独特的技能，以研究关键炎症介质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被确定在食管疾病，很少有信息是关于这种激活在这些疾病的分子机制。为了剖析相关途径，PI将通过正式的课程，掌握相关技术技能以及这些领域专家的指导来整合免疫学和肿瘤微环境的概念。候选人的导师Jonathan Katz博士是基因工程疾病小鼠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了额外的专业知识。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一流咨询委员会已经成立，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利用3D培养系统的补充体外系统来测试食管上皮细胞内IKK通路的激活产生增强食管发育不良、癌症和其他疾病的微环境的假设。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期），我们将确定上皮IKK信号在微环境中的作用，并在食管上皮-内皮细胞相互作用。这将在3D组织背景下使用新型转基因小鼠模型和原代食管上皮细胞进行。在目标2（K99/R 00期）中，我们将确定限制食管基质肌成纤维细胞扩增对上皮IKK？信号传导的要求。在这里，我们将利用卵巢特异性IKK基因敲除小鼠和3D培养。在目标3（R 00期），我们将确定食管上皮细胞炎症反应中STAT 3激活和IKK/NF B信号传导的功能相互作用。为了检查这些相互作用，我们将使用IKK敲入小鼠与STAT 3 floxed小鼠杂交。拟议的研究将由一流的和合议的智力环境，以及特殊的资源和设施提供给PI的支持。我们预计，这些研究将提供洞察调节正常食管上皮稳态的因素，微环境，以及在食管疾病，良性和恶性被破坏的途径。

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.