The Role of Transforming Growth Factor Beta Signaling in Inflammation-Dependent Colon Cancer

Persistent Link:
http://hdl.handle.net/10150/593463
Title:
The Role of Transforming Growth Factor Beta Signaling in Inflammation-Dependent Colon Cancer
Author:
Ball, Corbie
Issue Date:
2015
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Chronic inflammatory conditions such as Crohn's disease (CD) and Ulcerative colitis (UC) are risk factors for colon cancer. TGFβ has been shown to be dysregulated in colon cancer. Bacteria-induced inflammation is necessary for the induction of colon cancer in TGFβ mouse models. However, the mechanism by which TGFβ regulates the inflammatory response in these models is not well elucidated. It was our thought that we needed to be able to distinguish what was TGFβ dependent and what was inflammation dependent. To do this we created 2 colonies of Smad3 mice. One colony was housed with normal colonic bacteria (Smad3-uninfected animals) and the other colony (Smad3-infected animals) had chronic H. hepaticus infection. As previously seen the Smad3⁻/⁻- infected animals developed colitis and carcinoma (~40%). In the absence of H. hepaticus infection SMAD3 was found to negatively regulate TLR4 expression. This was then exacerbated with the addition of H. hepaticus resulting extreme up-regulation of TLR4 and the downstream effectors IRAK4 and NF-κB in Smad3⁻/⁻-infected colonic tissues. Examination of adaptive immune regulation in this model demonstrated that SMAD3 was necessary for FOXP3 expression in H. hepaticus-infected splenocytes. Loss of SMAD3 resulted in up-regulation of IL17 and reduced iTreg populations. These data demonstrate the important role SMAD3 has in maintaining tolerance to microbial populations through both the innate and adaptive immune systems.
Type:
text; Electronic Dissertation
Keywords:
FOXP3; Inflammatory Bowel Disease; TGF-beta; TLR4; Cancer Biology; Colon Cancer
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Doetschman, Thomas

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleThe Role of Transforming Growth Factor Beta Signaling in Inflammation-Dependent Colon Canceren_US
dc.creatorBall, Corbieen
dc.contributor.authorBall, Corbieen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.abstractChronic inflammatory conditions such as Crohn's disease (CD) and Ulcerative colitis (UC) are risk factors for colon cancer. TGFβ has been shown to be dysregulated in colon cancer. Bacteria-induced inflammation is necessary for the induction of colon cancer in TGFβ mouse models. However, the mechanism by which TGFβ regulates the inflammatory response in these models is not well elucidated. It was our thought that we needed to be able to distinguish what was TGFβ dependent and what was inflammation dependent. To do this we created 2 colonies of Smad3 mice. One colony was housed with normal colonic bacteria (Smad3-uninfected animals) and the other colony (Smad3-infected animals) had chronic H. hepaticus infection. As previously seen the Smad3⁻/⁻- infected animals developed colitis and carcinoma (~40%). In the absence of H. hepaticus infection SMAD3 was found to negatively regulate TLR4 expression. This was then exacerbated with the addition of H. hepaticus resulting extreme up-regulation of TLR4 and the downstream effectors IRAK4 and NF-κB in Smad3⁻/⁻-infected colonic tissues. Examination of adaptive immune regulation in this model demonstrated that SMAD3 was necessary for FOXP3 expression in H. hepaticus-infected splenocytes. Loss of SMAD3 resulted in up-regulation of IL17 and reduced iTreg populations. These data demonstrate the important role SMAD3 has in maintaining tolerance to microbial populations through both the innate and adaptive immune systems.en
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectFOXP3en
dc.subjectInflammatory Bowel Diseaseen
dc.subjectTGF-betaen
dc.subjectTLR4en
dc.subjectCancer Biologyen
dc.subjectColon Canceren
thesis.degree.namePh.D.en
thesis.degree.leveldoctoralen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorDoetschman, Thomasen
dc.contributor.committeememberDoetschman, Thomasen
dc.contributor.committeememberMartinez, Jesseen
dc.contributor.committeememberNelson, Marken
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