Treatment And Prevention Of Glaucoma By The Protein PRDX6

Nigar Fatma, PhD
University of Nebraska Medical Center (Omaha, NE)
Year Awarded:
2009
Grant Duration:
April 1, 2009 to September 30, 2011
Disease:
Glaucoma
Award Amount:
$93,991
Grant Reference ID:
G2009038
Award Type:
Standard
Award Region:
US Midwestern

Unveiling The Role Of Peroxiredoxin 6 In Maintaining Trabecular Meshwork Homeostasis

Summary

Progression of glaucoma appears to be related to overstimulation of certain genes that control the matrix surrounding cells in a part of the eye, called the Trabecular Meshwork (TM).This overstimulation occurs when TM cells face oxidative stress due to reduced levels of antioxidant(s). By supplying Peroxiredoxin 6, PRDX6, an antioxidant protein, we will be able to restore these over modulated genes by blocking oxidative stress-induced deleterious signaling.

Details

Recent evidence implicates that the oxidative stress plays a role in cause and progression of various ocular diseases including glaucoma, and suggests that aged cells are prone to this damage due to diminished expression of antioxidants. The eye is constantly exposed to radiation, atmospheric oxygen and environmental chemicals, and these factors continuously generate free radicals. If not quenched, this increases local accumulation of free radicals in the cellular microenvironment and causes ocular cell damage that leads to pathological changes. Glaucoma is a major eye disease causing blindness. One of the most important events in glaucoma is the elevation of intraocular pressure, which is associated with the specialized cells of the eye, called trabecular meshwork (TM). These cells are responsible for maintaining normal intraocular pressure and any abnormality or damage to the cells results in the development of glaucoma. Using human TM cell as a model system, Dr. Fatma will discover the major factor(s) responsible for the initiation of disease process and she will document how the changes in expression level of peroxiredoxin (PRDX)6, a multifunctional protective protein, influence the vulnerability of TM cells against oxidative stress, and document how reduced expression of PRDX6 in these cells, is one of the causes of TM cell damage/ abnormality that in turn yields to elevated intraocular pressure (IOP) and to glaucoma. In the extension of this project, she will reveal whether a delivery of PRDX6 could reverse these changes. Overall, successful completion of this project will have a significant impact toward the efforts in developing newer means of therapy for glaucoma that should in turn, reduce the economic burden and other complication as well as may be an asset for developing counties in treating or postponing glaucoma.

Research Updates

One of the most important events in glaucoma, a major eye disease causing blindness, is the elevation of intraocular pressure which is associated with the specialized cells called trabecular meshwork (TM). These cells are responsible for maintaining normal intraocular pressure and any abnormality or damage to the cells resulting from the development of glaucoma. We found that Peroxiredoxin (PRDX) 6, a multifunctional protective protein, is highly expressed in normal TM cells, but its expression is significantly reduced in TM cells in eyes with glaucoma. We surmised that reduced expression of PRDX6 in glaucoma cells may be a cause of initiation of patho-physiology in TM cells. Importantly, we observed that TM cells from individuals with glaucoma show structural changes and abnormal expression of certain proteins. These abnormalities of TM cells could be reversed following external treatment with PRDX6. Our data is encouraging and may provide a base for future treatments/preventions of glaucoma.

Publications

Fatma, N., Kubo E., Toris C.B., Stamer W.D., Camras C.B. and Singh, D.P. (2009) PRDX6 attenuates oxidative stress-and TGF -induced abnormalities of human trabecular meshwork cells. Free Radical Research. 43, 783-795. PubMed Icon Google Scholar Icon

Tulsawani, R., Kelly, L.S., Fatma, N., Chhunchha, B., Kubo, E., Kumar, A. and Singh,D.P. (2010) Neuroprotective effect of peroxiredoxin 6 against hypoxia induced ganglion cell damage. BMC Neuroscience. 11, 125-136** PubMed Icon Google Scholar Icon

Chhunchha B, Fatma N, , Bhargavan B, Kubo E, Kumar A, Singh DP. Specificity protein, Sp1-mediated increased expression of Prdx6 as a curcumin-induced antioxidant defense in lens epithelial cells against oxidative stress. Cell Death and Disease. 2011 [PMID:nd]

Fatma N, Singh P, Chhunchha B, Kubo E, Shinohara T, Bhargavan B, Singh DP. Deficiency of Prdx6 in lens epithelial cells induces ER stress response-mediated impaired homeostasis and apoptosis. Am J. Physiol. Cell Physiol. 2011, 301:C954-67*** PubMed Icon Google Scholar Icon

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