Center for Vision Research 1998 Progress Report
The following information is to bring you up-to-date on the progress of the Center for Vision Research in the Department of Ophthalmology. 1998 was a banner year for us in terms of scientific, financial, and organizational accomplishments.
Financial and Organizational Accomplishments in 1998:
During 1998, the Center for Vision Research in the Department of Ophthalmology passed all other medical school departments in terms of peer reviewed grant support per scientist and per square foot of research space. We have made outstanding progress and have opportunities to expand our strong core of vision scientists. With this momentum, we hope to reach our goal of establishing a world-class center for clinical and basic research in vision. 1999 will be another exciting year of important accomplishments for our team
January:
Four-year award by the Research to Prevent Blindness Foundation to support all aspects of vision research (Total Award: $200,000).
February:
Central New York Lions (Section 20 Y-1) vote to make the Department of Ophthalmology its major fund-raising objective for the future (Initial Commitment: $250,000).
March:
National Eye Institute of the National Institutes of Health awards a four-year research grant to Dr. Robert Barlow. NEI/NIH has now provided Dr. Barlow with 29 years of continuous support from NEI (Total Four-Year Award: $1,128,064).
May:
Scientific Advisory Board meets to evaluate the Center for Vision Research. Board Members:
- John E. Dowling, Ph.D. Harvard University
- Thaddeus P. Dryja, M.D. Harvard University
- Debora B. Farber, Ph.D. UCLA
- Alan M. Laties, M.D. University of Pennsylvania
- Torsten Weisel, M.D. Rockefeller University
- Robert H. Wurtz, Ph.D. National Eye Institute
June:
October:
Four-year Career Development Award from Research to Prevent Blindness for Eduardo C. Solessio, Ph.D. to join the Center for Vision Research. Start date: April 1, 1999 (Total Award: $165,000).
December:
Vision 2000 campaign passed the million-dollar mark.
Submitted proposal to Research to Prevent Blindness for support of Mr. James Hitt, student in the M.D./Ph.D. Program, for two years of support of his dissertation research.
Initiated the process of identifying a first-rate candidate who would be a worthy nominee for a Jules and Doris Stein Research to Prevent Blindness Professorship.
Scientific Accomplishments:
Scientists at the Center for Vision Research are employing powerful, state-of-the-art techniques in genetics and molecular biology to investigate leading causes of blindness. The 21st Century will begin with scientists mapping the human genome years ahead of schedule. Because many causes of blindness result from genetic defects, we are isolating critical genes and developing laboratory models for cloning and studying the abnormalities that these genes cause. The final step is to explore genetic and drug therapies to alleviate these abnormalities.
Major Areas of Research:
Regulation of Retinal Genes:
How is a normal retina made? It arises from the correct sequential activation of specific genes that cause precursor cells to divide and differentiate into rods and cones and other retinal cells. A major goal of ours is to use techniques of molecular biology to understand this complex process. Specifically, we are examining the "genetic switches" that control the expression of genes that synthesize the visual pigment molecules in rods and cones. The genetic switch has two components: transcription factors and promoters. The transcription factors regulate gene expression by binding to a DNA sequence, called a promoter. This past year, our team discovered promoters of genes that synthesize proteins in rods of the South African clawed frog, Xenopus. This discovery provides a powerful tool for us to study the molecular mechanisms that underlie retinal degeneration and lead to blindness.
Production of Transgenes:
How do genetic mutations cause blindness? By linking the DNA of a mutant gene with the DNA of the rod-specific promoters described above, we are producing "foreign" or transgenes. This past year our team successfully developed a technique for analyzing mutant retinal genes. The technique transplants the transgene into the retina of a Xenopus embryo to produce a transgenic animal that expresses the mutant gene in its rods. By combining electrophysiology, confocal microscopy and biochemistry, we are studying how the products degrade the function of the retina and causes blindness. We are focusing primarily on mutations of the gene for the visual pigment, rhodopsin, because such mutations have a devastating effect on vision. They cause the blinding disease retinitis pigmentosa. We hope to learn how these mutant genes cause blindness.
Gene Therapy:
Can the deleterious effects of mutant retinal genes be reduced or abolished? We are exploring the possibility of using gene therapy to reduce retinal degeneration by autosomal dominant mutations in the rhodopsin gene. Over 100 different mutations of the rhodopsin gene cause retinitis pigmentosa. Initial tests of our strategy in vitro are encouraging and may lead to a major therapy for all autosomal dominant forms of retinitis pigmentosa.
Glaucoma Genes:
Is glaucoma a genetic disease? A major type of open-angle glaucoma, pseudoexfoliative disease or PSX, is characterized by abnormal material on the lens capsule and other ocular surfaces. It occurs in all races, in persons usually over age 50 and occasionally in siblings. This is a lens-dislocating disease that causes glaucoma by the accumulation of a sticky abnormal material in the channels that control the outflow of aqueous humor. During this year, our group isolated a growth factor and identified the site of an enzyme important in the production PSX. Guided by the known protein of the elastic microfibril complex, we have targeted several candidate genes with hope of identifying a mutant factor. To this end, we have collected blood samples from single patients with PSX and as many sibling groups as possible. If the mutant factor is identified, we will then explore various molecular biological techniques, as gene therapy, to alleviate the effects of this type of glaucoma.
Corneal Genes:
Some forms of corneal dystrophies result from mutant genes. Our team has successfully identified a gene responsible for multiple corneal dystrophies. Investigations are underway to determine the specific corneal changes produced by the gene.
Molecular Basis of Vision:
How do visual pigments capture photons and convert the light energy into electrical signals? How do these pigments signal photons of different wavelengths, and how do they maintain their stability? These questions get at the root of our ability to see light, distinguish color and detect very dim lights. Using the tools of molecular biology to change the structure of the human visual pigments, we have gained insight into how the genes of the eye enable us to see color. Over the past year, we have expressed the genes for human visual pigments in a primate cell line and successfully recorded the very earliest electrical events initiated by photon absorption. By expressing mutant genes, we hope to learn how they may cause blindness and disrupt our ability to see. In addition, we are using the transgene technology described above to try and understand how a single visual pigment molecule can be sensitive to the thermal energy of our bodies. Some of the mutations in visual pigment genes that cause the degenerative retinal disease retinitis pigmentosa also impair the exquisite stability of the visual pigment molecule. This past year, we successfully introduced the transgenes into Xenopus. We are now growing the animals to a sufficient size to study their photoreceptors. We hope to learn if the loss in stability causes retinitis pigmentosa or is merely associated with it. The answer should lead to a better understanding of the etiology of some forms of this blinding disease.
Neural Code for Vision:
How does the eye signal the brain? In the past two years, our team made a discovery about the electrical signals that the eye sends to the brain. By constructing a realistic cell-based model of a retinal network, we successfully deciphered the neural code an eye sends to the brain. We used the horseshoe crab eye as a model system because more is known about it than the eye of any other animal. With our computational approach, we discovered that the eye transmits to the brain robust "neural images" of objects having the size, contrast, and motion of potential mates. Neural coding by this relatively simple eye helps explain how horseshoe crabs find mates and should lead to a better understanding of how more complex retinas, such as ours, function. The applications are far reaching. They include strategies for designing prosthetic devices for individuals who are blinded by retinal dysfunction.
Circadian Modulation of Retinal Function:
What is the function of ocular clocks? All vertebrate eyes contain biological clocks that cycle on a 24-hour period. Over the past several years, we have developed many model systems for investigating their role in vision. In one, the eye of the Japanese quail, we discovered that the ocular clock modulates the functional organization of the retina, shifting the eye from cone dominance during the day and rod dominance at night. We further discovered that a major neurotransmitter of the brain, dopamine, mediates these circadian changes. Because ocular clocks are known to control important metabolic functions of the retina, their dysfunction may contribute to some forms of retinal degeneration. Members of our team recently showed that a retinal clock controls the transcription of the gene for a cone visual pigment. We are now tracing the pathway of clock control gene expression with the hope of understanding how its disruption may lead to retinal degeneration.
The primary mission of the Center for Vision Research (CVR) is to enhance the research and training efforts of the basic and clinical vision scientists in the Central New York area. Secondary objectives are to facilitate collaborative studies among this community and attract other vision scientists to it.
|
