Project: Research project

Project Details


DESCRIPTION: The broad, long-term goal of this
work is to understand the molecular basis of hereditary retinal
degenerative diseases, which involves identification of the disease genes,
demonstration of the specific nature of the gene defects, and elucidation
of the pathophysiologlogical mechanisms involved, all of which may enable
gene replacement therapy in the future. Among the various inherited
retinal degenerative diseases that lead to blindness in man, gyrate atrophy
(GA) serves as a unique model because knowledge of the underlying
biochemical defect, i.e. a generalized deficiency of the mitochondrial
enzyme ornithine animotransferase (OAT), has enabled us to take a
relatively straightforward approach to tackling this disease at the gene
level. Specific Aims 1 and 2 Analysis of the OAT gene and its expression in GA
cases: correlation of the gene defects to disease phenotypes. GA is a
disease that exhibits considerable heterogeneity at the clinical level.
Molecular genetic analysis of GA cases by us and others are revealing a
remarkably complex picture in which not one, but a variety of different
mechanisms of OAT gene inactivation results in disease. Almost every case
analyzed so far has provided valuable new information not only about the
disease but also on fundamental mechanisms of gene expression and
regulation. For this reason, analysis of GA cases will be pursued.
Patient tissues will be analyzed at the DNA, RNA and protein levels. The
specific nature of each defect, be it gene deletion, rearrangement, point
mutation or other changes will be identified. Subtle gene changes such as
point mutations will be tested functionally for their effects on OAT in
order to confirm type of mutation revealed (by us and others), the
frequency of its occurrence in all of our cases will be established and
compared with clinical findings, to determine if conclusions can be drawn
concerning the type of mutation and the disease phenotype that results from
it. Specific Aim 3. Investigation into the pathophysiological mechanisms of
GA. The precise mechanism by which the OAT defects lead to the
chorioretinal degeneration, or even which cell types are primarily
affected, are still not known, largely due to unavailability of eye tissue
from patients and lack of an animal model. Ongoing projects will be
continued in which attempts are being made to reproduce the OAT deficiency
state of GA through inactivation of endogenous OAT in vitro and in vivo.
The in vitro approach involves transfer of antisense expression OAT gene
into cultured cells of various types including retinal pigment epithelium,
and biochemical analysis of the effects of OAT inactivation. in vivo OAT
inactivation, achieved by a combination of the antisense and transgenic
approaches, is an attempt to construct a mouse model of GA which will be
analyzed at multiple levels. Elucidation of the pathophysiological basis
of GA will not only help in understanding this disease but, in view of the
similarity of GA to other retinal degenerative diseases such as retinitis
pigmentosa (RP), may also shed some light on possible mechanisms involved
in RP. Finally, elucidaiton of the molecular and pathophysiological
mechanisms of GA will render this disease one of the best models of
hereditary ocular diseases for consideration of gene replacement therapy.
Effective start/end date9/30/919/29/92


  • National Institutes of Health: $164,005.00


  • Medicine(all)


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.