Date of Award

5-1-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Graduate School of Biomedical Sciences

First Advisor

Robert Wordinger

Abstract

Primary Open Angle Glaucoma (POAG) is a leading cause of blindness affecting over 70 million people worldwide. The most important risk factor for developing POAG is elevated intraocular pressure (IOP), which results from increased resistance of aqueous humor (AH) through the trabecular meshwork (TM) outflow pathway. Transforming growth factor- beta II (TGF-β2) is elevated in the AH and TM of glaucoma patients. Recent evidence indicate an extracellular BMP antagonist, gremlin, regulates BMP signaling and TGF-β2 activity. Follistatin (FST), another secreted BMP antagonist is recognized for its ability to bind BMPs and their type I receptor, sequestering BMP signaling. The purpose is to evaluate the presence and relevant activity of follistatin in TM tissues and cells. We hypothesize expression of follistatin in human trabecular meshwork cells alters the expression of extracellular matrix (ECM) deposition seen in the pathogenesis of glaucoma.

First, we examined differential FST expression in human trabecular meshwork cells and tissues. We observed a significant increase in expression of FST in glaucomatous as compared to normal protein and mRNA expression.

Next, we determined if FST could be induced upon treatment of exogenous TGF-ß2 protein in human TM cells. Studies showed TGF-ß2 up-regulated FST mRNA transcript in a time dependent manner. FST protein secretion was increased in a time and does dependent manner.

Third, we assessed FST effects on induction or inhibition of ECM proteins in human TM cells. ECM protein and mRNA expression was time dependent; nevertheless the response of ECM protein to FST treatment is different depending on isoform presence. Additional studies will be done to further elucidate these findings.

Lastly, we evaluated FST-288 and FST-315 inhibition of BMP4 attenuation of TGF-ß2 induced ECM expression. Data suggest FST-315 to suppress BMP-4 effects on TGF-ß2 induced ECM and FST-288 enhanced BMP-4 effects on TGF-ß2 induced ECM. The goal is to evaluate additional factors that contribute to the pathogenesis of POAG and assess how these factors can provide possible therapeutic mechanisms for the treatment of glaucoma.

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