Assistant Professor of Surgery, Section of Ophthalmology
Department of Surgery
University of Chicago
5841 S. Maryland Ave.,
Abbott 109 (MC2114)
Chicago, IL 60637
Phone: 773-702-5305
FAX: 773-702-4442
Email:
Translational research, which is a marriage between basic science and clinical investigation, is being carried out in our program with the goal of making significant contributions to the development of novel molecularly targeted treatments for retinal disease. The aim of our research program is to use genomics in a multi-faceted and interdisciplinary, systems-oriented approach to understand the molecular basis of common blinding retinal conditions, such as diabetic retinopathy, age-related macular degeneration and retinitis pigmentosa. Vision loss is the most feared disability, and the anticipated numbers of affected individuals with retinal disease over the coming years is staggering. Numerous ophthalmologic conditions have been identified and exquisitely described, however, the basic underlying pathogenic mechanisms remain to be determined. Using cell lines, patient samples, and donor eyes we are conducting genome-wide association studies; cellular screening experiments with small molecules; genome-wide RNA interference; and DNA expression analyses in order to identify the molecular mechanisms that contribute to retinal disease.
Age-related Macular Degeneration.
The completion of the human genome has ushered in a new era that allows
for evaluation of the molecular perturbations of a disease on a global
level. The thrust of systems biology is to take the genetics parts list
of the human genome and begin to assemble the biological circuits important
in normal physiology that become aberrant in disease states. Age-related
macular degeneration (AMD) not only has a hallmark clinical appearance
but also a characteristic genetic signature. In our studies we will define
the molecular signature of AMD to identify pathways critical to its pathogenesis
by employing a systems-based approach using global gene expression data
combined with high-throughput cellular screening. Using functional genomics,
we will identify novel molecular pathways potentially amenable to intervention
that should improve the treatment and/or prevention of AMD.
Retinitis Pigmentosa.
Retinitis pigmentosa (RP) is a family of inherited disorders characterized
by the progressive death of photoreceptors, which leads to vision loss
and eventual blindness. Scientists have presently identified over 29 genes
that are factors in causing RP, but remarkably, only a fraction of them
play a direct role in photoreceptor cells. The remaining genes are expressed
either in neighboring cells or are associated with mutant proteins detectable
throughout every cell of the body. Interestingly, however, the genes that
have been associated with RP share a common ability to activate apoptosis,
or programmed cell death, in photoreceptors. Though it is not clear how
these diverse genes trigger the common cascade of steps that result in
photoreceptor cell death, recent studies suggest that suppression of the
apoptotic pathway may promote photoreceptor survival. Using a cellular
model of RP, we will use an automated, efficient procedure to screen hundreds
of thousands of small molecules and perform genome-wide RNA interference
(RNAi) screening to identify those molecular compounds and genes that
may be able to prevent apoptosis in RP. Eventually, results from the screenings
will be extended to animal models with the goal of developing new therapies
to better treat RP in humans.
Diabetic Retinopathy.
Diabetic retinopathy is the leading cause of irreversible visual loss
in working age adults in America. Currently, there is limited knowledge
of the molecular underpinnings of this disorder. Preliminary work suggests
that there is a significant genetic component to diabetic retinopathy
yet to date no genes have been reliably associated with the development
of the sight threatening complications of this disorder. Elucidation of
the genetic basis of diabetic retinopathy will be necessary to not only
provide novel targets for treatment but also to suggest potential mechanisms
for its secondary prevention. The overarching objective of the study is
to identify those genetic elements that predispose to the development
of the sight threatening complications of diabetic retinopathy including
proliferative diabetic retinopathy and diabetic macular edema. Our research
studies employ a multifaceted approach to this problem by performing genome-wide
association studies in three separate, ethnically diverse cohorts of type
1 and type 2 diabetic individuals with severe eye disease. Subsequently,
we will carry out functional studies on cells and studies on donor eyes
to test candidate molecules discovered in the initial genetic studies.
In another line of research on diabetic retinopathy, we hypothesize that Wnt/ß-catenin signaling may become dysregulated in the setting of diabetes and may play a primary pathogenic role in diabetic retinal complications. The overall goal of this study is to examine the role of canonical Wnt signaling in the regulation of retinal endothelial cell function in the diabetic state. Our studies should reveal critical molecular factors underlying the pathogenesis of diabetic retinopathy that may facilitate the identification of novel therapeutic targets.
