The role of microenvironment in esophageal epithelial homeostasis

Project: Research project

Project Details

Description

This proposal describes a three-year independent program for the development of an academic basic science research career in gastroenterology, and is the application for the R00-phase of my grant entitled “The role of microenvironment in esophageal epithelial homeostasis” (1 K99 DK094977). The overarching goal of this proposal is to study the role of the key inflammatory mediator IKKβ in the regulation of the esophageal microenvironment. The significance of this proposal lies in (a) the prevalence of esophageal disorders, which are among the most common ailments in the United States and the world and (b) the important and emergent roles of IKKβ/ΝFκB signaling in the control of the microenvironment and of essential cellular processes in numerous tissues and cell types, including the esophagus. While activation of cytokines, chemokines, and inflammatory mediators has been identified in esophageal diseases, little information is available about the molecular mechanisms and the consequences of this activation in these diseases. To dissect the relevant
pathways, the PI will integrate concepts from immunology and the tumor microenvironment. The PI is an expert in genetically-engineered mouse models of disease, esophageal squamous cell biology, signal transduction, and transcriptional regulation. During the mentored phase of this grant, the PI has acquired additional expertise in three-dimensional culture, angiogenesis, fibrosis, and the regulation of the microenvironment. Here, we will take advantage of new mouse models and complementary in vitro systems utilizing 2D culture system to test the hypothesis that activation of the IKKβ pathway within esophageal epithelial cells produces a
microenvironment that potentiates esophageal inflammatory diseases. To explore these processes, we will undertake two interrelated Specific Aims. In Aim 1, we will determine the requirement for epithelial IKKβ signaling in limiting expansion of esophageal stromal myofibroblasts. Here, we will utilize esophageal-specific
IKKβ knockout mice that are crossed with dominant negative p38 MAPK mutant mice, and 2D culture. In Aim 2, 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 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.
StatusFinished
Effective start/end date8/6/157/31/18

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases (5R00DK094977-05)

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