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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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"[The National Eye Institute core center at TSRI] is not about curing a disease, but, rather, understanding the disease process and applying this fundamental knowledge to developing treatments for diseases that cause visual loss."

Martin Friedlander














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