The cornea provides the majority of the refractive power required to focus the incoming light on the retina and functions as a barrier protecting the eye from the environment. The cornea must maintain the proper radius of curvature and clarity to function properly. Preserving these properties is not an easy task because the cornea is exposed to the environment and as such it is subject to abrasions, infections and ultraviolet light. Due to the fact that the cornea is the principal source of refractive power it is subjected to surgical procedures to improve or restore vision. All of these factors are capable of causing inflammation resulting in either transient or permanent corneal edema or scarring that compromise the ability to see clearly. Corneal diseases and injuries are the leading cause of visits to eye care clinicians and have compromised the vision of more than 250 million people worldwide, leading to blindness in over 6 million. The goal of this grant is to characterize a newly identified group of proteins that are responsible for the production of superoxide by corneal cells. Superoxide is one of a group of molecules referred to as reactive oxygen species (ROS). These molecules not only exert oxidative stress on tissues but also regulate normal cellular functions.
The aims of this grant focus on the mechanisms by which corneal cells generate superoxide and the mechanism(s) through which it affects the functions of corneal stromal cells. We will examine the proteins composing a newly discovered protein complex in corneal cells called NADPH oxidase. Knowledge of the structure of the proteins of the complex is a key to understanding how to regulate its activities. We will determine the cellular location and the contribution of the complex to total cellular production of superoxide.
The second aim will investigate how the activity of the NADPH oxidase is regulated. Regulation of the activity of the complex in critical because over production of superoxide can be detrimental to cells but cell survival may be compromised if to little is produced.
The third aim will determine how superoxide regulates cell survival. Survival of all the corneal cell types is critical to maintaining corneal function. We believe that superoxide plays a critical role in the mechanism(s) by which growth factors and cytokines influence corneal cells. Completing the aims of this grant will provide insight required to develop new drugs to regulate superoxide production and maintain the corneal function following infection, injury or surgery.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AED-F (04))
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Mckie, George Ann
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Medical College of Wisconsin
Schools of Medicine
United States
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Rizvi, Farhan; Heimann, Tom; O'Brien, William J (2012) Expression of NADPH oxidase (NOX) 5 in rabbit corneal stromal cells. PLoS One 7:e34440
Rizvi, Farhan; Heimann, Tom; Herrnreiter, Anja et al. (2011) Mitochondrial dysfunction links ceramide activated HRK expression and cell death. PLoS One 6:e18137
O'Brien, William J; Heimann, Tom; Rizvi, Farhan (2009) NADPH oxidase expression and production of superoxide by human corneal stromal cells. Mol Vis 15:2535-43