Director: Joe G. Hollyfield, Ph.D.
Director, Department of Ophthalmic Research
Cole Eye Institute
9500 Euclid Avenue, i32
Office telephone: 216.445.3252
Goals and projects
Research in the laboratory of Joe G. Hollyfield, Ph.D., seeks to develop a model in rodents that would mimic the conditions found in age-related macular degeneration AMD.
Oxidative damage and inflammation are postulated to be involved in AMD. However, the molecular signal(s) initiating AMD are unknown. We have been able to generate AMD-like lesions in mice following immunization with mouse serum albumin adducted with carboxyethylpyrrole, an oxidation fragment of docosahexaenoic acid previously found in eye tissue and plasma from AMD patients. Mice develop antibodies to this hapten; fix complement component 3 in Bruch's membrane; accumulate drusen below the retinal pigment epithelium during aging; and develop lesions in the retinal pigment epithelium mimicking the blinding end-stage atrophy characteristic of dry AMD. We hypothesize that these mice are sensitized to the generation of this hapten in the outer retina where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This model provides a platform for dissecting the molecular pathology of oxidative damage and the immune response contributing to the initiation of this disease.
The Role of Drusen in Macular Degeneration
The goal of this research is to define in molecular terms the linkage between the accumulation of soft drusen below the retinal pigment epithelium (RPE) in the macula and the increased risk of developing age-related macular degeneration (AMD). The presence of soft drusen in the macula is the hallmark risk factor for developing AMD. Surprisingly little is known of the composition or origin of drusen. To this end, a novel method for drusen isolation has been developed that allows the collection of microgram quantities of drusen from donor eye tissue.
At the time of isolation, different drusen sub-types can be identified and separated for use in studies that will characterize their molecular composition. The diagnostic utility of drusen in AMD can be likened to that of blood levels of cholesterol in atherosclerosis. The presence and abundance of drusen, like the level of cholesterol in the blood, indicates the degree to which a patient is at risk for developing the disease.
Because of the relationship of drusen and AMD, understanding the composition of drusen sub-types will provide important information on possible pathways that are causally involved in drusen development. Novel proteins or common modifications of proteins present in drusen should provide insight as to potential drug targets of therapeutic agents to treat AMD. The current research is focused on exploiting this drusen isolation procedure to define the molecular composition, distribution and cellular origin of drusen sub-types in normal and AMD tissues.
The Function of Hyaluronan in IPM Organization and Macular Degeneration
The goal of this research is to define the structure-function relationships of specific molecules in the interphotoreceptor matrix (IPM), a unique matrix that surrounds the extensions of photoreceptors projecting from the outer surface of the retina. Collectively, molecules in this matrix and their interactions establish the microenvironment required for the maintenance of photoreceptor function. This matrix must be porous, allowing the movement of metabolites between photoreceptors and RPE, while at the same time serving as a structured scaffold that supports the alignment of the photoreceptors. The entire IPM complex also serves as an attachment bridge with a tensile strength permitting a physical link between the retina and RPE.
Our ultimate goal is to define the functional role of the molecules in this matrix and determine how they support the health and survival of photoreceptors and the RPE. Of primary importance for retinal function is the role of the IPM in the attachment of the retina to the RPE. Understanding the nature of these interactions and their breakdown is of fundamental importance in understanding retinal detachment. Because of the strategic location of this matrix, it can be anticipated that defects in molecules residing in this compartment may be causally involved in some forms of macular degeneration and retinitis pigmentosa.