Pathobiology of Astrocytes and Microglia in Glaucoma
About the Research Project
Program
Award Type
Standard
Award Amount
$49,576
Active Dates
April 01, 1995 - March 31, 1998
Grant ID
G1995432
Summary
Primary open-angle glaucoma is a painless disease of the eye which gradually destroys sight. One of the major risk factors of the disease process is the raised pressure that occurs within the eyeball. This increased intraocular pressure adversely affects the retina which is the light-sensitive layer at the back of the eye. The retina consists of a network of neural cells that first convert light energy into electrical signals. These signals are relayed to the brain by specialized ganglion cells and their long processes called axons which leave the eye from a single region known as the optic nerve. The elevated pressure in the eyes of patients who have glaucoma causes degeneration of the ganglion cells in the retina and of the axons in the optic nerve thereby impeding transmission of the light stimulus. In addition to the neural cells and their processes, other accessory cells are present in the retina and optic nerve. Two of the main types of accessory cells are designated as microglial cells and astrocytes, and they are recognized as having a supportive role for the normal function of the neural cells. By synthesizing a variety of active biologic chemicals, known as cytokines, a complex interaction exists among astrocytes, microglia, and neurons. Previous experimental studies have shown that two cytokines, namely gamma- interferon (y-IFN) and transforming growth factor-beta 1 (TGF-ß1), have a pivotal role in maintaining the normal balance between the actions of astrocytes and those of microglial cells, and a disturbance in this equilibrium can lead to damage of neurons by the activated microglial through several mechanisms. For example, the secretion of y-IFN by astrocytes stimulates the microglial cells to produce a number of agents which not only injure the neurons, but also induce proliferation of astrocytes. In contrast, the production of TGF-ß1 by both types of accessory cells suppresses activation of the microglial cells and thus can inhibit their neuron-destructive actions. Based on the available evidence, we advance a hypothesis which states that the elevated pressure in eyes with primary open-angle glaucoma influences the synthesis of cytokines by microglial cells and astrocytes and that, through a cascade of events, the altered biology of these cells contributes to the degeneration of ganglion cells and their axons and hence, to the loss of sight. The specific aims of this research proposal are designed to investigate the effect of increased pressure on the synthesis of y-IFN and TGF-ß1 within astrocytes and microglial cells, as well as on the amounts of cytokines produced. To accomplish these aims, we will employ an animal model of raised eye pressure as well as tissue from human donor eyes with a history of primary open angle glaucoma. By using modem molecular biology techniques, we measure synthesis of ?-IFN and TGF-ß1 by quantitating the levels of the molecules (messenger ribo- nucleic acid or mRNA) within the cells that are responsible for, and control, the synthesis of these cytokines, and we use specific markers to quantitate the amounts of y-IFN and TGF-ß1 present in the retina and optic nerve of the eye. We anticipate that elevated pressure causes an increase in the levels of the mRNA for y-IFN and a decrease in those for TGF-ß1, which results in their increased and decreased production, respectively. The long-term goals of our research are to study the precise mechanisms by which astrocytes and microglial cells cause damage to the neuronal cells. This is a novel unexplored approach for the investigation of destruction of ganglion cells and their axons; it can open up new avenues for the prevention of loss of sight in primary open-angle glaucoma, and possibly also for the development of adjunctive therapy in the regeneration of injured neuronal cells. The results we obtain may also provide insights into the ways in which visual loss occurs in other types of glaucomatous disease of the eye.
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