Apical Polarity Complex Signaling in Inflammation in Intestinal Epithelia

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Recent published work in our laboratory has shown a profound downregulation of atypical PKC in intestinal epithelial cells under TNF? stimulation, in the DSS model of murine colitis, and in Inflammatory Bowel Disease patients. In this project we will analyze mechanistically the consequences of aPKC loss on cellular functions, signaling pathways, and molecular effectors, known to be essential in the pathophysiological of IBD in these cells. Our preliminary data strongly indicate that a decrease in aPKC activity comparable to that observed in the animal model and in patients, is sufficient to trigger activation of the classic I?B pathway independently of TNFR. This observation opens the possibility that signaling downstream of aPKC may establish a negative feedback that keeps epithelial cells in an inflamed condition even if the original cytokine stimulaton is removed. If our hypothesis is correct, breaking this cycle may help to rapidly correct barrier defects and cytokine secretion by epithelial cells, which would be desirable in chronic intestinal inflammation. Moreover, since these pathways are specific to epithelial cells, understanding them may allow tissue-specific interventions. The mechanistic aspects and the consequences of this phenomenon will be studied in Aim 1. Our preliminary data also shows that a similar transient event occurs in epithelial wounds, suggesting the hypothesis that it may also be involved in the early stages of epithelial restitution, which will b tested in Aim 2. Finally, the molecular mechanisms studied in aims 1 and 2 will be analyzed in in the context of an animal model of colitis in Aim 3. Altogether the project is expeced to establish a totally novel signaling pathway, identify its normal function, and bring new, as ye unsuspected possible therapeutic targets to modulate the epithelial response to inflammation.
StatusFinished
Effective start/end date1/1/076/30/16

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $302,266.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $305,319.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $85,680.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $321,129.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $332,775.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $305,319.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $302,440.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $301,232.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $332,775.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $332,775.00

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