The role of microenvironment in esophageal epithelial homeostasis

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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.