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TGF-beta and CTGF regulation of extr...

Hyer, Elizabeth Gore.

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TGF-beta and CTGF regulation of extracellular matrix synthesis in tissue fibrosis: Analysis of in vitro and in vivo models.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	TGF-beta and CTGF regulation of extracellular matrix synthesis in tissue fibrosis: Analysis of in vitro and in vivo models./
Author:	Hyer, Elizabeth Gore.
Description:	214 p.
Notes:	Chair: Maria Trojanowska.
Contained By:	Dissertation Abstracts International63-11B.
Subject:	Biology, Animal Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3070112
ISBN:	9780493898780

TGF-beta and CTGF regulation of extracellular matrix synthesis in tissue fibrosis: Analysis of in vitro and in vivo models.
Hyer, Elizabeth Gore.

TGF-beta and CTGF regulation of extracellular matrix synthesis in tissue fibrosis: Analysis of in vitro and in vivo models. - 214 p.

Chair: Maria Trojanowska.

Thesis (Ph.D.)--Medical University of South Carolina, 2002.

Transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) are profibrogenic growth factors associated with the pathogenesis of most fibrotic diseases. The goal of this work was to characterize the common and distinct profibrogenic effects of these growth factors using in vitro and in vivo models of systemic sclerosis (SSc) and renal fibrosis. Both growth factors potently induce extracellular matrix (ECM) synthesis in SSc fibroblasts but via distinct mechanisms. In vitro, TGF-beta stimulates matrix synthesis in normal and SSc fibroblasts, whereas CTGF selectively induces ECM expression in SSc fibroblasts only in cooperation with insulin. Furthermore, SSc fibroblasts express increased TGF-betaRI levels. This altered TGF-beta receptor ratio significantly correlates with unresponsiveness to inhibition of collagen basal levels by blocking TGF-betaRII signal transduction and may suggest an alteration in autocrine TGF-beta signaling in these cells. In the cell types contributing to pathologic ECM deposition in renal fibrosis, TGF-beta and CTGF induce similar profibrotic effects in mesangial cells but have divergent functions in epithelial cells. Only TGF-beta stimulates collagen whereas both TGF-beta and CTGF induce tenascin-C, an ECM protein associated with epithelial-mesenchymal transdifferentiation (EMT), which is a process implicated in the generation of increased interstitial fibroblasts associated with renal fibrosis. Thus, CTGF's profibrogenic actions may distinctly facilitate EMT with a less pronounced effect on collagen deposition, whereas TGF-beta is a known mediator of both EMT and excessive ECM deposition in tubular epithelial cells. TGF-beta receptor ratios are also modulated in vivo in the remnant kidney model of renal fibrosis. TGF-betaRII levels remain elevated with disease progression, whereas increases in TGF-beta and TGF-betaRI levels are transient. CTGF levels are induced subsequent to TGF-beta, remaining elevated upon the onset of fibrosis with kinetics similar to TGF-betaRII. Collectively, our studies suggest that alterations in TGF-beta receptor levels may be a common mechanism in tissue fibrosis by which TGF-beta upegulates its signaling pathway to achieve its profibrotic functions. In addition, these studies suggest that CTGF is a potent inducer of ECM but likely in the context of other profibrotic signaling pathways, such as TGF-beta or insulin/insulin like growth factors (IGFs), and may serve to perpetuate the fibrotic response initiated by TGF-beta.

ISBN: 9780493898780Subjects--Topical Terms:

1017835
Biology, Animal Physiology.

TGF-beta and CTGF regulation of extracellular matrix synthesis in tissue fibrosis: Analysis of in vitro and in vivo models.
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245 1 0 $a TGF-beta and CTGF regulation of extracellular matrix synthesis in tissue fibrosis: Analysis of in vitro and in vivo models.
300 $a 214 p.
500 $a Chair: Maria Trojanowska.
500 $a Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5065.
502 $a Thesis (Ph.D.)--Medical University of South Carolina, 2002.
520 $a Transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) are profibrogenic growth factors associated with the pathogenesis of most fibrotic diseases. The goal of this work was to characterize the common and distinct profibrogenic effects of these growth factors using in vitro and in vivo models of systemic sclerosis (SSc) and renal fibrosis. Both growth factors potently induce extracellular matrix (ECM) synthesis in SSc fibroblasts but via distinct mechanisms. In vitro, TGF-beta stimulates matrix synthesis in normal and SSc fibroblasts, whereas CTGF selectively induces ECM expression in SSc fibroblasts only in cooperation with insulin. Furthermore, SSc fibroblasts express increased TGF-betaRI levels. This altered TGF-beta receptor ratio significantly correlates with unresponsiveness to inhibition of collagen basal levels by blocking TGF-betaRII signal transduction and may suggest an alteration in autocrine TGF-beta signaling in these cells. In the cell types contributing to pathologic ECM deposition in renal fibrosis, TGF-beta and CTGF induce similar profibrotic effects in mesangial cells but have divergent functions in epithelial cells. Only TGF-beta stimulates collagen whereas both TGF-beta and CTGF induce tenascin-C, an ECM protein associated with epithelial-mesenchymal transdifferentiation (EMT), which is a process implicated in the generation of increased interstitial fibroblasts associated with renal fibrosis. Thus, CTGF's profibrogenic actions may distinctly facilitate EMT with a less pronounced effect on collagen deposition, whereas TGF-beta is a known mediator of both EMT and excessive ECM deposition in tubular epithelial cells. TGF-beta receptor ratios are also modulated in vivo in the remnant kidney model of renal fibrosis. TGF-betaRII levels remain elevated with disease progression, whereas increases in TGF-beta and TGF-betaRI levels are transient. CTGF levels are induced subsequent to TGF-beta, remaining elevated upon the onset of fibrosis with kinetics similar to TGF-betaRII. Collectively, our studies suggest that alterations in TGF-beta receptor levels may be a common mechanism in tissue fibrosis by which TGF-beta upegulates its signaling pathway to achieve its profibrotic functions. In addition, these studies suggest that CTGF is a potent inducer of ECM but likely in the context of other profibrotic signaling pathways, such as TGF-beta or insulin/insulin like growth factors (IGFs), and may serve to perpetuate the fibrotic response initiated by TGF-beta.
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