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The two laboratories also study the role of the tumor suppressor
genes p53 and p21 in these integrin-mediated angiogenic pathways
and the antiangiogenic properties of the noncatalytic carboxy-terminal
end of a matrix metalloproteinase enzyme called "PEX." PEX
is a naturally occurring 29-kD protein that binds to and prevents
localization of full-length, active matrix metalloproteinase-2
to the tip of proliferating new blood vessels. Recombinant
forms of PEX inhibit angiogenesis in several laboratory models,
which Friedlander has observed in vivo.
Recently, Friedlander's laboratory has initiated a collaboration
with Skaggs Institute investigator Paul Schimmel to study
the mechanism and clinical usefulness of fragments of tryptophanyl
tRNA synthetases in inhibiting angiogenesis. "We are very
excited about this project since it provides the opportunity
to use gene- and cell-based therapies to deliver a molecule
that, in our hands, is the most potent anti-angiogenic we
have worked with to date," says Friedlander.
In the laboratory, he maintains a long-standing interest
in studying the mechanism through which proteins are asymmetrically
integrated into the cell membrane, a problem he initially
became interested in while working in the laboratory of Nobel
laureate Gunter Blobel at The Rockefeller University. "There
are a number of inherited retinal degenerations that result
in profound visual loss and have as their genetic basis mutations
in integral membrane proteins such as rhodopsin and peripherin,"
says Friedlander. By studying the topogenic signals that serve
to target, integrate and tanslocate these molecules into the
cells of the eye he hopes to gain a better understanding of
how the retina degenerates in diseases like retinitis pigmentosa
and Leber's Congenital Amaurosis.
In collaboration with Immunology Associate Professor Glen
Nemerow, Friedlander's group also has a program in Ocular
Gene Therapy. Using modified adenoviral and cell-based delivery
vectors, the goal of this program is to specifically target
genes to different eye cell types in the treatment of inherited
retinal degenerations and acquired neovascular diseases.
"While we have been learning much about the underlying gene
defects in the inherited retinal degenerations and have identified
potential therapeutic targets in neovascular diseases, we
are still faced with significant challenges in effectively
and efficiently delivering therapeutics to the posterior segment
of the eye where these disease processes occur," says Friedlander.
"Gene and cell-based delivery represent novel approaches to
drug delivery that we are highly encouraged by."
From the Cornea to the Core
Applying basic science to clinically relevant problems in
vision is something that Friedlander is involved with in an
institute-wide fashion as well, as the principal investigator
of the new Core Center for Vision Research at TSRI, which
began operations on June 1 of this year.
Earlier this year, the National Eye Institute (NEI) announced
multi-year funding for the core, which will support shared
resources for 11 TSRI researchers who have independent programs
in vision science funded through the NEI and six researchers
from the University of California, San Diego (UCSD).
"Each investigator is an outstanding scientist in their
own particular field," says Friedlander. "We found ourselves
with a large group of individuals who all knew something about
some small aspect of the visual system. It's precisely the
sort of expertise that the NEI looks for in funding programs
like ours."
A microarray core module will produce DNA "chip" microarrays
that can be used for observing changes in gene expression
during the course of normal and pathological changes in the
eye. Similarly, a proteomics core module will provide global
analysis of all the proteins expressed. A microscopy and imaging
core module will allow the phenotypic state of eye tissue
to be studied in conjunction with the expression data that
comes from the microarray and proteomics cores.
Investigators using the microscopy and imaging core will
be able to take advantage of new technologies in order to
expand existing research, for example a state-of-the-art multiphoton
scanning laser confocal microscope.
Friedlander hopes that the center will strengthen and expand
existing basic research and facilitate professional interactions
among TSRI investigators, UCSD scientists, and their clinical
counterparts at Scripps Clinic and Scripps Memorial Hospital.
"So that they become aware of potential applications of their
research that may be related to diseases of the visual system,"
he says.
"The [core center] is not about curing a disease," he says,
"but, rather, understanding the disease process and applying
this fundamental knowledge to developing treatments for diseases
that cause visual loss."
Back to the Clinic
Inside the doctor's office a woman has come from far away
with a hole in her retina, complaining of white flashes and
sore eyes. She worries that sometimes whole cars disappear.
"[Can you] tell me," she says, "if I need more surgery?"
"Doctor—am I going blind?" she asks.
Friedlander looks into the back of her eye and says "no."
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