Studies

The dry or atrophic form of age-related macular degeneration, seen above in fundus photography and in a cross-sectional diagram, is the most common form of macular degeneration, accounting for about 90 percent of cases. Although this form of AMD does not usually cause severe vision loss, it can progress to the wet form, so patients who have it should see their ophthalmologist regularly.

1. AGE-RELATED MACULAR DEGENERATION

--Hollyfield Laboratory
--Personnel: Karen Shadrach, Long Li, Nikolas Neric, Xiaoping Yang, Vera Bonilha and Mary Rayborn

(a). 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.

(b). 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.

(c). Function of SPACR and SPACRCAN in the IPM and Macular Degeneration The goal of this research is to define the structure-function relationships of specific interphotoreceptor matrix (IPM) macromolecules, especially as they relate to supporting the maintenance, health and survival of photoreceptor cells of the retina and RPE, and their causal involvement in retinal disease. Much of the focus of this work will be on SPACR and SPACRCAN, two novel gene products present in the insoluble IPM.

--The Crabb Laboratory
--Personnel: John S. Crabb, Jiayin Gu, Xiaorong Gu, Kwok Peng Ng, Renganathan Kutralanathan, Xianglin Yuan, Xiuzhen Yue and Xianquan Zhan

(d). Proteomic Studies of Macular Degeneration The long-term goal of this research is to better understand the molecular mechanisms of drusen formation and Bruch's membrane thickening in age-related macular degeneration (AMD). The unifying hypothesis of the proposal is that protein modifications are causally involved in both processes. Drusen are extracellular deposits that form between the RPE and Bruch's membrane and confluent drusen constitute the hallmark risk factor for developing AMD. The progression of AMD might be slowed or halted if drusen and Bruch's membrane changes can be modulated. We seek to identify proteins and lipids in drusen and Bruch's membrane from healthy and AMD donor tissues and characterize associated protein modifications and reactive lipid fragments.

--Sears Laboratory
--Personnel: Jonathan Sears and George Hoppe

(e) Role of Glutaredoxin in Oxidative Stress in the RPE The broad long-term goal of this project is to investigate the hypothesis that oxidative injury to phospholipid substrate may impair RPE function and specifically inhibit the metabolic cooperation between the RPE and retina. The diverse redox protective mechanisms within the RPE create a complex system subject to feedback loops that may not respond to oral doses of antioxidants. Rather, a fundamental understanding of the molecular components of these protective systems is necessary to rationally design therapeusis. This investigation will seek to determine the importance of the enzyme glutaredoxin in conferring redox protection to the RPE.

[Back]