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| Research Statement |
Research Interests - The Photobiology Research Group investigates ocular aging as it relates to various disease states such as cataract in the lens and age-related macular degeneration. Our main interest is to study the role of light and oxygen in these maladies. Our approach is to investigate these processes in molecular detail and then apply that knowledge to an animal model. In this manner we hope to develop methods to retard or negate disease processes in the eye. Our group consists of scientists, clinicians and fellows which allows us to approach these problems with a full spectrum of expertise.
One of the salient features of ocular research is that it is specialized, with studies developed around specific ocular tissues such as the cornea, lens, retina etc. In a number of instances, though, there is a great deal of interdependence between various tissues. This is especially true for the amount and wavelength of light reaching each structure and the amount of oxygen available to each tissue. In humans both of these parameters vary with age and have been implicated in both aging and diseases of the eye. The main thrust of this laboratory is to determine the molecular mechanism(s) of aging and diseases in the eye; most notably, cataract formation in the lens and macular degeneration in the retina.
The human lens absorbs most UV light from reaching the retina. This is performed by the O-b-glucoside 3-hydroxykynurenine (3-HKG), which is only found in primate lenses. The presence of this compound in the human lens determines the spectrum of visible light reaching the retina which for humans starts at 400 nm. With age there is a loss of 3-HKG with a concomitant yellowing of lens proteins, increasing the photic load on the mature human lens and decreases the amount of blue light reaching the retina1. It is our contention that light plays a role in both aging and cataractous processes in the lens. One aging mechanism may be the photochemically induced attachment of 3-HKG to lens protein forming yellow photoproducts 2-4. In addition, cortical cataracts have been correlated with light exposure and this has been mechanistically verified by us 5-8. Other possible cataractous agents are nitrite from smoking9, which has been correlated with nuclear cataracts, and oxygen.
Although oxygen is essential for life, it can be deleterious to tissues when in excess. The definition of excess, though varies depending on the tissue. Oxygen freely diffuses across the cornea and the retina and has a range of normal physiological levels. In contrast the lens is almost anaerobic. How the eye accomplishes this is an active area of our research. Any increases in oxygen levels would compromise the stasis of the lens. Older patients undergoing hyperbaric oxygen treatment or have a vitrectomy invariably develop a nuclear cataract. It develops in that part of the tissue presumably because it is the oldest, contains less anti-oxidants and is therefore the most susceptible to oxidation. We have found that following a vitrectomy oxygen tension is increased in the rabbit lens. We have hypothesized that this explains the formation of a nuclear cataract after vitrectomies and may explain the formation of nuclear sclerosis in general.
With age and disease the retina also accumulates new material. This resides in the pigment epithelium and in general is called lipofuscin. A major component of this mixture has recently been identified as an orange fluorophore with the structure of a pyridinium bis-retinoid (A2E)10. The absorption maximum of A2E is at 430 nm (in RPE cells). It has been determined by us that light absorption of A2E can lead to the production of numerous reactive oxygen species 11-12 which, in the RPE, may lead to the observed deterioration in Stargardt's and AMD.
In addition to these molecular studies, we and our collaborators, have initiated studies on various other levels including; an epidemiological investigation of the effect of cataract removal on AMD, the non-invasive detection of oxygen tension in the eye and the fluorescence imaging of the retina. With these studies we will be able to better understand the mechanism and diagnose the progress of various ocular disorders.
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| Staff |
Clinical Professor:
John Merriam, M.D.
Staff Associate:
Lei Zheng, M.D.
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