The Role of Actin Scavenger System in Aqueous Outflow Facility

Glaucoma is a devastating medical problem for millions of individuals and is a leading cause of blindness worldwide. Elevated intraocular pressure (IOP) is a major risk factor for glaucomatous optic nerve damage. Thus, nearly all current glaucoma therapy is directed toward lowering IOP. The anterior chamber of the eye is filled with an aqueous fluid called aqueous humor, which is continuously secreted and drained from the eye by the ciliary body and the chamber angle tissue of the eye respectively. The aqueous humor serves two important functions in maintaining normal vision, by nourishing the avascular tissues of the anterior chamber of the eye including lens and cornea, and maintaining the convex shape of the cornea. To ensure the convex shape of the cornea critical for normal vision, the pressure exerted by the aqueous humor should conform to a certain optimum value, also called the normal intraocular pressure. Under normal physiological conditions, IOP is maintained by the resistance to flow of the aqueous through the angle tissue consisting of the trabecular meshwork and Schlemm’s canal, which together comprise the outflow pathway. In glaucoma patients, there is abnormal resistance to aqueous humor outflow through trabecular meshwork and the general agreement is that a rise in the resistance of the outflow pathway constitutes a basis for increased IOP. Currently very little is known in terms of the reasons underlying increased resistance in the outflow pathway. In this proposal I present a mechanistic hypothesis that could potentially account for elevations in IOP, and offer a means for drug development through biotechnology. During normal aging and, with inflammation, injury and infection, the cells of the anterior chamber tissues may die and release cellular contents into aqueous humor. Under normal physiological conditions, the outflow pathway tissue has the capacity to digest and clear such cell debris from the aqueous humor, but under certain pathological conditions, the balance between the clearing capacity of outflow pathway and accumulation of cell debris may be compromised. Under such conditions then, aqueous humor may accumulate excessive cell debris and cell contents such as proteins and nucleic acids. Certain cellular components such as actin, the major structural protein of the cell and DNA, have a tendency to self-aggregate and thereby and potentially clog the outflow pathway. The ensuing impairments in outflow pathway function would then be expected to lead to increased resistance of the aqueous humor, directly contributing to increased IOP. To circumvent such deleterious possibilities, nature has also created a scavenging mechanism to sequester and clear these proteins and DNA from circulating and other bodily fluids. The actin scavenger system consists of two proteins called gelsolin and Ge-globulin. These two molecules act in concert to clear actin from body fluids. Extracellular gelsolin, an actin-binding protein, severs aggregated actin, while Ge-globulin binds unpolymerized actin and removes it from the circulation. Therefore, these two molecules have been thought to have tremendous clinical relevance for clearing the actin from circulating body fluids. In this study, we hypothesize that this actin scavenger system may have a very important role in maintaining the normal IOP and also have potential therapeutic significance for treatment aimed at reducing ocular pressure in certain forms of glaucoma. Our main objective in this study is to understand the physiological role of actin scavenger system in the regulation of intraocular pressure and also to explore whether its insufficiency can lead to increased IOP. To accomplish these objectives, I plan to determine the age related changes in the actin scavenger system of aqueous humor of human and pig cadaver eyes and determine the effects of actin scavenger molecules (gelsolin and Gcglobulin) on the functionality of the outflow pathway. I believe that these studies will potentially provide new insight into the role of actin scavenger system in regulation of outflow facility and etiology of increased IOP and novel approaches toward developing medical treatment for glaucoma.