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EXTRACELLULAR MATRIX REGULATION IN RETINAL PIGMENT EPITHELIAL CELLS AND ROLE IN RETINAL FIBROSIS
by
Rima Khankan
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
December 2006
Copyright 2006 Rima Khankan
Object Description
| Title | Extracellular matrix regulation in retinal pigment epithelial cells and role in retinal fibrosis |
| Author | Khankan, Rima Rachad |
| Author email | rkhankan@doheny.org |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pathobiology |
| School | Keck School of Medicine |
| Date defended/completed | 2006-10-24 |
| Date submitted | 2006 |
| Restricted until | Restricted until 12 Dec. 2008. |
| Date published | 2008-12-12 |
| Advisor (committee chair) | Hinton, David R. |
| Advisor (committee member) |
Hofman, Florence M. Tsukamoto, Hidekazu Triche, Timothy J. Humayun, Mark |
| Abstract | The research in our laboratory is focused on the response of the retinal pigment epithelium (RPE) to injury and how RPE structure and function are altered in pathologic retinal disorders such as proliferative vitreoretinopathy (PVR). RPE cells regulate the balanced homeostasis of growth factors and extracellular matrix (ECM) proteins. We hypothesized that fibronectin EDA (FN-EDA), an ECM molecule implicated in excessive scar formation and chronic fibrosis, is expressed and regulated by activated RPE cells and thus plays an essential role in PVR pathogenesis.; Using primary cultures of human RPE cells, we detected FN-EDA protein under normal conditions but not in serum-deprived cells. We found that serum increases the content of FN-EDA in these cultures in a dose-dependent manner. Therefore, all subsequent experiments were carried out in the absence of serum to eliminate any serum-related effects on FN-EDA regulation by RPE cells. In frozen sections of normal human retinas, though FN-EDA was present in retinal and choroidal vessels, the RPE monolayer was devoid of FN-EDA. These results suggest that resting RPE cells do not express FN-EDA.; In growth factor-stimulated cultures of RPE cells, we found that FN-EDA mRNA and protein were induced by transforming growth factor-[beta]2 (TGF[beta]2) in a time- and dose-dependent manner but not by connective tissue growth factor (CTGF). By co-stimulating RPE cultures with TGF[beta]2 and CTGF, we demonstrated that CTGF, through its N-terminal domain, augments the TGF[beta]2-induced expression of FN-EDA at the protein level. Using CTGF domain-specific antibodies, we blocked this synergistic effect. By protein-protein interaction studies, we established that CTGF directly interacts with TGF[beta]2 and its receptor TGF[beta]RII at its N- and C-terminal domains, respectively. Our results therefore suggest that CTGF modulates TGF[beta]2 responses and provide further evidence for CTGF as a down-stream mediator of TGF[beta]2.; Finally, we demonstrate that FN-EDA is abundantly expressed in PVR membranes in a pattern that co-localizes with TGF[beta]2 and CTGF. FN-EDA upregulates type I collagen in cultures of RPE cells as do TGF[beta]2 and CTGF. These findings suggest that FN-EDA is an important mediator of retinal fibrosis, making it a potential target for therapy. |
| Keyword | fibronectin-EDA; retinal pigment epithelial cells; proliferative vitreoretinopathy |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m188 |
| Contributing entity | University of Southern California |
| Rights | Khankan, Rima Rachad |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-Khankan-20061121 |
| Archival file | uscthesesreloadpub_Volume29/etd-Khankan-20061121.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | EXTRACELLULAR MATRIX REGULATION IN RETINAL PIGMENT EPITHELIAL CELLS AND ROLE IN RETINAL FIBROSIS by Rima Khankan A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PATHOBIOLOGY) December 2006 Copyright 2006 Rima Khankan |
