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VITRONECTIN MISFOLDING AND AGGREGATION: IMPLICATIONS FOR
THE PATHOPHYSIOLOGY OF AGE-RELATED DISEASES
by
Thuzar Myo Shin
____________________________________________________________________
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)
August 2007
Copyright 2007 Thuzar Myo Shin
Object Description
| Title | Vitronectin misfolding and aggregation: implications for the pathophysiology of age-related diseases |
| Author | Shin, Thuzar Myo |
| Author email | thuzar@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pathobiology |
| School | Keck School of Medicine |
| Date defended/completed | 2007-06-25 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-07-27 |
| Advisor (committee chair) |
Chen, Jeannie Hinton, David R. |
| Advisor (committee member) |
Langen, Ralf Triche, Timothy Stallcup, Michael |
| Abstract | Classic amyloidopathies are characterized by the accumulation of misfolded proteins in the form of plaques. Whilst fibril deposition is pathognomonic for amyloidopathies, recent data suggest that prefibrillar species may mediate the development and progression of disease. Soluble amyloid oligomers exhibit similar morphologic and cytotoxic properties, suggesting a shared pathogenic mechanism among amyloid proteins. The oligomer-specific A11 antibody is a useful tool to study amyloid diseases which lack abundant fibril deposition. As part of a collaborative study on the pathophysiology of age-related macular degeneration, we studied protein misfolding in human ocular drusen and demonstrated the presence of prefibrillar oligomers using the A11 antibody. However, the oligomer-forming protein in drusen has not yet been identified. Historically, the amyloidogenic protein is oftentimes the most abundant protein near or within the disease plaque. Vitronectin is one of the most abundant drusen proteins, is contained in all drusen, and is also present within the insoluble deposits associated with Alzheimer disease, atherosclerosis, systemic amyloidoses, and glomerulonephritis. These deposits stain positive with thioflavin, indicating an underlying protein misfolding process. The extent to which vitronectin contributes to amyloid formation within these plaques and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin misfolding and aggregation is significant since the formation of oligomers and fibrils is a common ability of amyloid proteins, although they share neither sequence nor native structural homology. In this study, we tested the hypothesis that vitronectin is amyloidogenic.; Our results demonstrate that human vitronectin readily forms spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Vitronectin fibrils contain a C-terminal proteaseresistant domain which likely contains the essential residues for amyloid formation. Consistent with our data that illustrate the inherent propensity of vitronectin to selfassociate in vitro, vitronectin fragments were detected in the insoluble fraction of human atherosclerotic plaques, suggesting that vitronectin aggregation likely occurs in vivo. Our results put forth the possibilities that accumulation of misfolded vitronectin may contribute to amyloid plaque formation and the pathophysiology of age-related amyloid diseases. |
| Keyword | drusen; aging; age-related macular degeneration; amyloid; fibril; recombinant protein |
| 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-m694 |
| Rights | Shin, Thuzar Myo |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Shin-20070727 |
| Archival file | uscthesesreloadpub_Volume40/etd-Shin-20070727.pdf |
Description
| Title | Page 1 |
| Full text | VITRONECTIN MISFOLDING AND AGGREGATION: IMPLICATIONS FOR THE PATHOPHYSIOLOGY OF AGE-RELATED DISEASES by Thuzar Myo Shin ____________________________________________________________________ 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) August 2007 Copyright 2007 Thuzar Myo Shin |
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