Senior Scholar Award in Aging
The Chromophore Regeneration Pathway in Age-related Macular Degeneration.
Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population. However, little is known about the etiology and molecular pathophysiology of AMD. AMD is characterized clinically by mottling of the retinal pigment epithelium (RPE) at the posterior pole of the fundus and scattered drusen, which is an opaque yellow excrescence located between Bruch’s membrane and the RPE. Progressive changes cause leakage of serous fluid and blood from the choroid capillary layer, small serous detachments of the RPE, and neovascularization. Eventually, destruction of the sensory retina and fibrous scaring occur. Unfortunately, effective treatment options are limited and consist mainly of laser photocoagulation therapy.
One of the hallmarks of age-related change in the RPE is the accumulation of an autofluorescent material called lipofuscin. Two of the major fluorophores in lipofuscin (A2E and iso-A2E) were recently isolated from aged human eyes and their structures were determined. The exact mechanism of the in vivo genesis of A2E is not known. However, it almost certainly involves Schiff base formation between the aldehyde of all-trans-retinal (ATR) and the 1o-amine of ethanolamine, or more likely phosphatidylethanolamine.
The fact that ATR is the precursor of A2E raises an interesting paradox. If the chromophore regeneration pathway of the retina is working properly, then ATR should not accumulate at all in the RPE. If ATR is the main precursor of A2E, then how can it form in the RPE cells since ATR is normally not found in the RPE cells in significant concentration? What is the source of the ATR? There are two main possibilities. First, it could be from the normal chromophore regeneration pathway that is somehow defective. For example, ATR could accumulate if the conversion of ATR to all-trans-retinol by retinal dehydrogenase and NADPH in the photoreceptor cell was blocked and excess ATR was transported and taken up by the RPE cells. Alternatively, the excess ATR could gain entry to the RPE cells by phagocytosis of photoreceptor cell membranes that contain an abnormal amount of ATR relative to all-trans-retinol as they are shed at the distal end of the photoreceptor cell.
Another possibility is that the pathway outlined above may not apply specifically to cone cells and their underlying RPE. Rods and cones seem to be different with respect to retinoid biochemistry, and cone pigment regeneration may follow a different pathway than that of the rod. This possibility will be addressed by isolating RPE from different zones of the retina and trying to define biochemical and molecular biological differences in the RPE in contact with rods versus that in contact with cones. We will also study the molecular biology of cell-type specific signaling between photoreceptor cells and RPE cells. How do the photoreceptor cell and the RPE cell communicate to regulate the chromophore regeneration pathway?
In summary, our basic research program will focus on the possibility that an age-related defect in the normal chromophore regeneration pathway contributes to the molecular pathophysiology of AMD. The hypothesis underlying our work is that the defect involves communication between the photoreceptor cone cells and the RPE as it relates to retinoid metabolism.