| Geoff Lewis: Current
Research
Geoff Lewis> Current Research
Understanding the mechanisms behind the loss and recovery of vision
following retinal detachment and reattachment has been the focus of our
studies for many years. In the normal retina, the light sensitive outer
segments of the photoreceptor cells are interdigitated with the highly
specialized apical processes of the retinal pigment epithelial cells.
Numerous cellular and molecular interactions occur across this interface,
including the transport of oxygen and nutrients. The physical separation
of these 2 layers (retinal detachment) is a serious cause of visual impairment
in humans and can result from many different causes including trauma,
retinal tears, and complications from diseases of the eye. For many years,
photoreceptor outer segment degeneration was considered the primary effect
of detachment and their imperfect regeneration the most likely cause of
continued visual defects after successful reattachment. What we have learned,
however, is that detachment leads to a number of other cellular events
including: photoreceptor cell death, Müller cell proliferation and
hypertrophy, remodeling of photoreceptor synaptic terminals and a concomitant
outgrowth of neurites from second- and third-order neurons. These events,
which have their beginnings within minutes of creating the detachment
and continue for as long as the retina remains detached, most likely contribute
to the degree of visual recovery following reattachment surgery.
Retinal reattachment may be thought of in a simplistic way of returning
the retina to a "normal" configuration. Our most recent studies
of reattachment in animal models and comparisons to human reattachments
indicate that this is almost certainly not true. We have shown that early
reattachment can stop or slow many of the detrimental changes initiated
by detachment, however, once initiated, many of these changes, in particular
the "plastic" changes observed in some neurons, do not immediately
return to normal. In addition, reattachment appears to initiate an entirely
new set of potentially deleterious cellular responses not observed in
the detached retina. Because of this we have begun examining the use of
various supplemental agents given during detachment to aid in the recovery
of the retina. Two agents, brain derived neurotrophic factor and oxygen,
have shown promise in achieving this goal. Other projects in the lab include
examining detached retinas from humans, pursuing a model of retinal detachment
in a cone dominant retina, and assessing the functional recovery of the
retina using electrophysiological techniques.
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| The "end feet" of
Muller cells dramatically remodel following retinal detachment as demonstrated
with antibodies to the intermediate filament proteins GFAP (green) and
vimentin (red). In the normal retina (left), the end feet label primarily
with anti-vimentin. (The lateral processes of the astrocytes label only
with anti-GFAP.) At 3 and 7 days after detachment (center and left) the
structural remodeling of the end feet is accompanied by an increase in
GFAP and vimentin, with a shift to more anti-GFAP labeling |
Many of these studies would not have been possible without help from
our collaborators, Jonathan Stone (oxygen studies; University of Sydney),
Charanjit Sethi and David Charteris (human retinas and animal models of
human disease; Moorfields Eye Hospital, London), Gerry Jacobs (electrophysiology
studies; UCSB), Stuart Feinstein and Monte Radeke (neurotrophin studies;
UCSB), Don Anderson and Linc Johnosn (human retina studies; UCSB), and
Bob Avery (human retina studies; Cottage Hospital, SB). |
