Year of Award

2009

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Biomedical Sciences

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Elizabeth Putnam

Commitee Members

Andrij Holian, Stephen Lodmell, Curtis Noonan, Mark Pershouse

Keywords

Asbestos, Collagen, Fibrosis, SPARC

Abstract

Pulmonary fibrosis involves the invasion of lung tissue with fibrotic, scar tissue and affects roughly five million people total worldwide. Fibrotic development in the lung has several causes, including chronic inflammatory diseases, infections, medical compounds, and environmental agents. There is no known cure for the disease, but only therapies to improve quality of life. Scar tissue formation must be targeted in order to begin to provide any type of cure for fibrotic diseases. In this study, asbestos was used to induce pulmonary fibrosis in a mouse model and gene expression studies were then performed to identify potential candidate genes involved in asbestos response. One gene with the potential to regulate the fibrotic response is SPARC (secreted protein acidic and rich in cysteine), a matricellular protein involved in tissue repair, extracellular matrix (ECM) regulation, cellular proliferation, and cellular adhesion. The goal of this project was to determine the role of SPARC in fibrosis development after asbestos exposure, specifically targeting how lack of SPARC expression can influence collagen production. I hypothesize that SPARC is a necessary component involved in the fibrotic response to asbestos through an influence on collagen deposition in the lung. I have found that the expression of SPARC is increased in the lungs of C57Bl/6 wild-type mice exposed to asbestos. This increase in expression correlates to higher collagen deposition in the lung. The absence of SPARC in these treated mice resulted in a reduction of the level of collagen deposition back to baseline. To determine the therapeutic potential of these findings, SPARC expression was reduced by small interfering RNA (siRNA) in wild-type mice already suffering from fibrosis. Collagen deposition in the fibrotic mice that received the SPARC siRNA vector showed a significant decrease in collagen accumulation when compared to those that did not receive the vector. Overall, these results indicate that expression of SPARC is a significant step in the development of lung fibrosis through the modulation of collagen deposition and therefore, SPARC may be a potential therapeutic target.

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© Copyright 2009 Aubrey Meghan Smartt