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Director: Neal S. Peachey, Ph.D.
Department of Ophthalmic Research
Cole Eye Institute
9500 Euclid Avenue, i32
Office telephone: 216/ 445-1942
Fax: 216/ 445-3670
Email: peachen@ccf.org
Members of the Peachey lab, from left, are Sherry Ball, Ph.D., Elisa Bala, M.D., Jiang Wu, M.D., Neal Peachey, Ph.D., Minzhong Yu, M.D., Ph.D., and Ruth Yarnevic, B.S.
Goals and
projects under way in the Peachey Lab:
Mouse
Retinal Electrophysiology
As the
mouse has become the premiere laboratory model for retina research, it has
become increasingly important to develop objective measures of retinal function
that can be used to evaluate the function of different classes of retinal
cells.
We have
adopted a noninvasive technique that has been used to investigate the origins
of visual dysfunction in human hereditary and acquired retinal disorders. The
ERG (electroretinogram) is the mass electrical response of the retina to light.
In the research laboratory, the response provides a sensitive means to evaluate
experimental therapies for retinal disease, which can be repeated at different
time points on the same animal. In addition, the ERG is used to characterize
the effects of pharmacological manipulation or introduction of gene defects.
By
controlling the conditions under which stimuli are presented, the activity of
the rod or cone visual pathways can be monitored independently. Based on
contributions from a number of investigators, it is now possible to relate the
different components that comprise the rod-mediated ERG to the major cell types
of the rod visual pathway. This knowledge has led to a comprehensive model of
the rod ERG which finds wide application.
In
comparison, the components that underlie the mouse cone ERG have not been
identified. As a major focus of the CEI research program is macular
degeneration, we are using pharmacological agents that block transmission from
cone photoreceptors to second order neurons that comprise the cone pathway
(cone depolarizing bipolar cells, and the cone hyperpolarizing bipolar cells)
to determine the contribution of these cell types to the cone ERG. At the
completion of this work, we will define a model capable of relating the
components of the cone ERG to the cells that comprise the cone pathway.
In
collaboration with Alan D. Marmorstein, Ph.D., we have also developed a
noninvasive procedure for recording the electrical response of the retinal
pigment epithelium (RPE) to light. In comparison to the rod and cone ERGs
mentioned above, the RPE components are very slow, necessitating dc-recording.
This procedure will be particularly useful in characterizing rodent models
expressing mutant RPE genes.
Mouse Models of Congenital Stationary Night Blindness
For the past several years, we have been working with a naturally
occurring mouse model of complete congenital stationary night blindness
(CSNB1). This mutant, named nob, involves a defect in transmission from
rod and cone photoreceptors to depolarizing bipolar cells. The nob
mouse carries a mutation in the nyctalopin gene, which is also the gene
involved in human CSNB1. As the function of nyctalopin is unknown, studies are
under way to define the role of this protein in normal retinal function and
development.
We have also identified a mouse model of another form of human
disease, incomplete CSNB (CSNB2). The mouse model involves the CNS-specific
deletion of the gene encoding a subunit of the L-type calcium channel that
normally regulated release of glutamate at the photoreceptor terminal. These
mice develop the same phenotype seen in patients with CSNB2, which involve
mutations in the a 1F subunit. Studies are under
way to define the role of L-type calcium channels in ribbon synapse formation.
Evaluation of the Retina with a Sub-retinal Microphotodiode Array
This project concerns the tissue compatibility of a
subretinal microphotodiode array that has been developed in an attempt to
restore vision in patients blinded by diseases causing photoreceptor
degeneration. In these diseases, only the photoreceptors degenerate, sparing
the inner retinal neurons. The microphotodiode approach relies on electrical
stimulation of these inner retinal layers to propagate the visual signal
centrally.
In the course of evaluating several
implant designs, we have developed a body of data indicating that the implant
has good biocompatibility and have found that the use of specific materials for
implant fabrication results in a device that will respond consistently for up
to 3 years following implantation. While the implant induces disorganization of
the inner retinal cell layers, there is no loss of inner retinal neurons in the
implanted retina. In addition, the use of cytochemical markers has identified
subtle but reproducible changes in the distribution of inhibitory neurons in
the inner retina.
We are trying to determine the time
course over which these changes occur. The data derived from these studies will
provide valuable information on how the inner retina responds to the implant,
and may also define areas for implant design improvements.
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