FUNDING PERIOD: APRIL 1, 2001 - MARCH 31, 2002

Halyan Gong M.D., Ph.D.
Boston University School of Medicine
Boston, MA
Project: Schelemm's Canal Basal Lamina: A Variable Resistor?

Used aqueous humor leaves the eye through a specially designed filtration tissue known as the trabecular meshwork (TM). The part of this filter with the finest mesh is called the Juxtacanalicular region or simply the JCT. After flowing through the JCT, aqueous humor passes through the cells of the inner wall lining Schlemm's canal into the venous system. Most clinicians and most researchers believe that the principal site of the resistance to aqueous humor outflow is between the inner aspects of the JCT and the lumen of Schlemm's canal. Dr. Gong is focusing on the possible role of the basement membrane of Schlemm's canal in fluid outflow resistance. The basement membrane of Schlemm' s canal exhibits focal discontinuities. She has hypothesized that the normal flow of fluid might "dissolve" little holes in the basement membrane, because the basement membrane becomes more discontinuous in normal eyes when the flow pressure is increased. She is now investigating whether these changes fail to occur in glaucomatous eyes. If this is the case, a new cause for increased flow resistance will have been identified, setting the stage for additional studies to understand the molecular basis for increased resistance.

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Susan A. Keirstead, Ph.D.
University of Minnesota
Minneapolis, MNa
Project: Responses of Retinal Ganglion Cells to Optic Nerve Injury

Elevated levels of glutamate are known to kill retinal ganglion cells, and glutamate is found in high concentrations in the eyes of people and animals with glaucoma. The series of events that elevated glutamate triggers in retinal ganglion cells is not well understood, but it appears to be dependent on an influx of calcium ions into the cell. Dr. Keirstead is monitoring calcium concentration inside retinal ganglion cells before, during, and after optic nerve injury to determine if calcium increases as a result of axonal injury. She hypothesizes that axonal injury changes the way retinal ganglion cells regulate intracellular calcium, either by causing increases in calcium or by altering the ability of retinal ganglion cells to regulate calcium concentration. Using an in vivo technique she developed that mimics the clinical situation more closely than other techniques, she is monitoring calcium in real time with video imaging microscopy to provide a dynamic picture of the processes going on inside retinal ganglion cells. Dr. Keirstead is also examining support cells in the retina called Miller glial cells. She will examine the calcium responses of these cells to determine if they have any long-term functional changes in response to optic nerve injury that could adversely affect their support of retinal ganglion cells in pathological conditions. These experiments may provide a basis for the design of therapeutic protocols to prevent vision loss due to glaucoma. This project is a continuation of an AHAF-funded study by the same name, begun in 1999.

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Karen Qi Lee, Ph.D.
Pennsylvania State College of Medicine
Hershey, PA
Project: Optic Nerve Metabolism and Ocular Blood Flow

Glaucoma is associated with many risk factors, especially elevated intraocular pressure (IOP), but also older age, a family history of glaucoma, African ancestry, diabetes mellitus and vascular diseases. It is generally believed that ischemia plays an important role in the pathogenesis of glaucomatous optic nerve damage, but the mechanisms of how the ischemia occurs and causes retinal ganglion cell death is unknown. However, both ischemia and the cell death are associated with increased concentrations of glutamate and lactate in the vitreous fluid. Dr. Lee and her team are measuring these concentrations noninvasively in vivo using MRI and MRS (spectroscopy) scans. An animal model of ischemia is being used to evaluate the levels of lactate and glutamate in real-time using MRI, MRS, fluorescein fundus angiography and scanning laser Doppler flowmetry. It is hoped that the results will lead to a better understanding of the roles of glutamate and lactate in the ischemia and retinal ganglion cell death of glaucoma.

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Robert W. Nickells, Ph.D.
University of Wisconsin
Madison, WIn
Project: Molecular Mechanism of Retinal Ganglion Cell Death

The only treatment for glaucoma is to treat the primary risk factor for this disease, which is an
elevated intraocular pressure (IOP). Research efforts have been focussed on finding alternative treatments that will directly affect the survival of the retinal ganglion cells. Dr. Nickells has been defining the molecular biology of the process of ganglion cell death, with the goal that some of the biochemical events that occur in a dying ganglion cell could be manipulated to increase the chance of cell survival. When ganglion cells receive a stimulus to die, they activate a series of biochemical events that leads to their eventual suicide. These events can be broken into semi-sequential steps. Strategies aimed at blocking late steps in the process do not appear to offer promising treatments. Therefore, Dr. Nickells has chosen to study the earliest events in the cell death process. This is the period when normal gene expression is turned off. Dr. Nickells' earlier work has discovered that three known genes active in ganglion cells are turned off with nearly identical kinetics in dying cells. The first part of this study is to develop a more comprehensive method for identifying additional such genes. The second part of the project is to investigate the mechanism for turning these genes off, and to test possible pharmacological approaches for intervening in this process. The third part of the study is to find out if blocking the early down-regulation of gene expression has any positive impact on cell survival. If this can be accomplished, then blocking the early events in ganglion cell death may be a viable target for new treatments in glaucoma. This project is a continuation of Dr. Nickells' earlier AHAF-funded work, begun in 1999.

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Ivaylo R. Stoilov, M.D.
University of Connecticut
Farmington, Connecticut
Project: Role of CYP1B1-Retinoid in Congenital Glaucoma

Some newborns and infants are affected by an especially severe form of glaucoma called Primary Congenital Glaucoma (PCG). PCG is caused by an abnormal development of the anterior chamber angle of the eye. In previous studies, Dr. Stoilov has found that this disease is caused by mutations in the gene for Cytochrome P4501B1 (CYPlBl). Humans have more than fifty different cytochrome P450 genes. They are responsible for the synthesis of various hormones and for detoxifying drugs, alcohol, and other chemicals. Based on the substrate specificity of CYPlBl, Dr. Stoilov hypothesizes that CYP1B1 affects a little-known retinoid signaling pathway operating during the later stages of eye development. Dr. Stoilov's goal is to identify the enzymes involved in the CYPlBl pathway and study their expression during the development of the anterior chamber angle of the eye.

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