Improved treatments for age-related maculopathy (ARM), the leading cause of untreatable vision loss among the elderly in the developed world, lie in better understanding of early ARM. On the basis of our preliminary data, we hypothesize that early age-related maculopathy is an ocular form of atherosclerosis. According to this hypothesis, the pathophysiology of ARM involves two mechanisms similar to those that occur during aging and atherosclerosis in the inner wall of the large arteries: According to this hypothesis, the inner wall of the large arteries: an age-related deposition of serum-lipoprotein-derived esterified cholesterol and unesterified cholesterol (EC and UC) in association with extracellular matrix proteins; and a disease-related deposition of a UC-rich material with the participation of local cells. Using a unique resource for human donor eyes and a well-established animal model for experimental atherosclerosis, we propose three aims to test several predictions of this hypothesis. 1) In human eyes, we will determine how the EC and UC content of Bruch's membrane varies with age and retinal location, using filipin fluorescence and digital microscopy. We will identify EC-rich particles in Bruch's membrane by determining how solvents affect filipin fluorescence and ultra-structure. We will characterize the lipid composition of isolated Bruch's membrane using an enzymatic assay and gas-chromatography-mass spectrometry. 2) In human eyes, we will determine the morphology of membranous debris occurs in peripheral retina. We will determine the UC content of membranous debris and photoreceptor outer segments using filipin fluorescence, digital microscopy, and ultrastructural stereology. 3) In rabbit eyes, we will determine if an extended diet of cholesterol supplementation results in deposition of EC in Bruch's membrane EC, using autoradiography to localized systemically injected radiolabeled tyramine-cellubiose-low density lipoprotein in tissue sections. Results from these aims will be valuable in assessing the extent to which ARM and atherosclerosis share pathogenetic mechanisms with regard to the accumulation and source of extracellular cholesterol. This information is required in order to determine if effective treatments for atherosclerosis should be considered for the treatment of early ARM.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY006109-17S3
Application #
6938862
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
1990-07-15
Project End
2005-02-28
Budget Start
2002-08-01
Budget End
2005-02-28
Support Year
17
Fiscal Year
2004
Total Cost
$147,285
Indirect Cost
Name
University of Alabama Birmingham
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Neely, David; Zarubina, Anna V; Clark, Mark E et al. (2017) ASSOCIATION BETWEEN VISUAL FUNCTION AND SUBRETINAL DRUSENOID DEPOSITS IN NORMAL AND EARLY AGE-RELATED MACULAR DEGENERATION EYES. Retina 37:1329-1336
Litts, Katie M; Wang, Xiaolin; Clark, Mark E et al. (2017) EXPLORING PHOTORECEPTOR REFLECTIVITY THROUGH MULTIMODAL IMAGING OF OUTER RETINAL TUBULATION IN ADVANCED AGE-RELATED MACULAR DEGENERATION. Retina 37:978-988
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