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Congressional Justification for FY 2000
National Eye Institute
|Authorizing Legislation:||Section 301 and Title IV of the Public Health Service Act, as amended. Reauthorizing legislation will be submitted.|
This document provides justification for the FY 2000 Non-AIDS activities of the National Eye Institute (NEI). Justification of NIH-wide FY 2000 AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)."
In developing the sixth in the series of long-range plans for vision research, Vision Research-A National Plan: 1999-2003, the National Advisory Eye Council (NAEC), in conjunction with the vision research community, advocates for vision research, and staff of the National Eye Institute (NEI), set a vision for the NEI as we enter the new century.
This vision served to guide the development of the goals and objectives that will address our Nation's most pressing visual health needs while exploiting the most significant opportunities for progress. In addition to establishing the priorities for NEI-supported vision research over the next five years, the national plan identifies the progress that has been made and serves as the foundation for continuation of that progress. This justification for FY 2000 highlights some of the priorities for federally-funded vision research identified in the national plan and the areas of progress upon which they are based.
Science Advances and Future Research Directions
The retina is the complex, light-sensitive, neural tissue in the back of the eye that contains highly-specialized and metabolically active photoreceptor cells (rods and cones). These cells respond to light by emitting chemical and electrical signals. These signals are received by other retinal cells which process and transmit visual information via the optic nerve to the brain for decoding. The choroid is the underlying layer of blood vessels that nourish the retina. The retina and choroid are susceptible to a variety of diseases that can lead to visual loss or complete blindness These sight-threatening conditions include age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinitis pigmentosa, retinal detachment, uveitis (inflammation), and cancer (choroidal melanoma and retinoblastoma).
Age-Related Macular Degeneration. Age-related macular degeneration (AMD) is the leading cause of new blindness in persons over age 65. Based on recent advances, research is being directed toward the identification of genes which, when mutated, contribute to the development of AMD. Techniques of molecular genetics allow scientists to examine "candidate" genes to determine whether mutations occur with a higher frequency in persons affected by AMD than in unaffected persons. While such mutations might not by themselves be sufficient to cause AMD, they may contribute to the occurrence of AMD in the presence of other mutant genes or environmental insults. Scientists in the NEI intramural program will screen approximately 1000 patients and age-matched control individuals from the Age-Related Eye Disease Study (AREDS). AREDS is a large, multicenter, research program designed to improve our understanding of the predisposing factors, clinical course, and prognostic factors of AMD and cataract. DNA samples from the study's participants will be examined for mutations or sequence variants in a group of well-characterized genes known to be involved in a fundamental retinal function or to cause retinal disease. A repository of genetic material from the AREDS participants is being created to test candidate genes for AMD as they are identified. Extramural investigators will have access to this resource. Finding a genetic basis for AMD will increase our understanding of the pathophysiology of the disease and assist in developing new treatments or methods of prevention.
Prevention of Complications from Age-related Macular Degeneration. Another new direction for age-related macular degeneration research has been through NEI support for the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). This trial will assess the safety and effectiveness of laser treatment in preventing loss of vision among patients at high-risk for developing age-related macular degeneration. In addition to the primary outcome, which is visual acuity loss, quality of life will be assessed. Twenty-five clinical centers will conduct the study over the next five to seven years.
Retinal Pigment Epithelium-Specific Protein. The retinal pigment epithelium (RPE) is the tissue adjacent to the retina that supports many of the retina's metabolic functions. Intramural scientists identified and characterized an RPE-specific protein, RPE65, that has been shown to play an important role in the vitamin A metabolism in the retina. Other NEI-supported investigators have recently demonstrated that mutations in the human RPE65 gene are associated with Leber's congenital amaurosis, a disorder characterized by blindness at birth, and with autosomal recessive childhood-onset severe retinal dystrophies. The NEI intramural group has developed an RPE65-deficient mouse with a phenotype that parallels the human disorder. This new mouse model is important not only because it will be a very valuable system for understanding RPE biochemistry and the vertebrate visual cycle, but also because it provides a model to test possible therapies for the human diseases.
Retinopathy of Prematurity. Retinopathy of Prematurity (ROP) is a potentially blinding eye disorder of premature infants who typically weigh 2¾ pounds or less. ROP is associated with the growth of abnormal blood vessels that can lead to retinal scarring or detachment, resulting in vision loss. Annually, approximately 1100-1500 infants develop disease that is severe enough to require medical treatment. Although NEI-supported studies have demonstrated the effectiveness of cryotherapy as a treatment for severe ROP, the cause of the disease is still not well understood. Lighting levels in hospital nurseries have been suggested as a factor in the development of ROP, but previous research had been conflicting and inconclusive. To clarify this issue, the NEI sponsored a multicenter clinical trial, the Effects of Light Reduction on Retinopathy of Prematurity. In this study, a control group of infants experienced normal nursery lighting and another group wore specialized goggles--the equivalent of wearing very dark sunglasses-while in the same normal nursery lighting environment. Researchers found that reducing ambient light exposure did not alter the risk of developing ROP. Long-term followup of these infants, as well as those who participated in the cryotherapy treatment study, will continue. Additionally, in an effort to further improve treatment for ROP, another clinical trial is currently testing whether supplemental oxygen therapy in infants with moderate ROP will prevent the progression of the disease to the severe stage.
Autoimmune Diseases. Autoimmune diseases include multiple sclerosis, lupus, rheumatoid arthritis, diabetes and a group of sight-threatening ocular inflammatory diseases called uveitis. There is little known about the factors that determine susceptibility to autoimmune diseases. NEI intramural researchers have recently discovered that ocular-specific proteins known as antigens that trigger the body's immune response are also found in the thymus (a small organ that plays a role in development of the immune system) of certain animals. Thymic presence of antigens produces specific immunotolerance toward these proteins. These scientists found a correlation between thymic expression of ocular antigens and resistance against uveitis induced by these antigens. Animal species that contain the antigens in their thymus are resistant, while those that do not are susceptible to disease induction. Furthermore, the results show that the degree of susceptibility or resistance may depend on the relative amounts of the antigens present in the thymus. These results suggest, therefore, that susceptibility/resistance to autoimmune diseases is regulated by the absence/presence of certain self-antigens in the thymus. If these results are similar in human autoimmune diseases, they may open up a new avenue of research for therapeutic application.
Diabetic Retinopathy. The principal pathologic mechanism underlying catastrophic visual loss in diabetic patients is the abnormal proliferation of new blood vessels (angiogenesis) in the retina or the iris. Vascular endothelial growth factor and insulin-like growth factor-1 have been implicated in angiogenesis. This finding represents a new direction for diabetic retinopathy research. Vision scientists will are poised to make rapid progress in research on angiogenesis, because of the availability of very good animal models, the ability to visualize microvascular alterations at very early stages in both animals and humans, the ability to sample vitreous repetitively, and the ability to introduce drugs and biologics directly to the retina. NEI and several other institutes with an interest in angiogenic research have co-sponsored several recent program announcements and requests for applications. These activities will continue in FY 2000.
Gene Therapy for Retinal Degeneration. Dominantly inherited diseases are an especially challenging problem for development of gene-based therapies. Ideally, a defective gene could be replaced in a dominantly inherited disease in order to eliminate the deleterious protein product. Recently, two different strategies have been developed by NEI-funded investigators to attack this problem in the genetic disorder autosomal dominant retinitis pigmentosa (ADRP), one of a group of diseases in which the rod and cone photoreceptors degenerate and cause progressive visual loss. The most common form of ADRP results from mutations in rhodopsin, the light-sensitive protein in the rod photoreceptors. Several sites have been identified within the rhodopsin gene that can bind small DNA molecules and potentially interrupt the expression of the mutated protein. Another group of investigators has developed a ribozyme-based approach to photoreceptor cell rescue. Ribozymes are small RNA molecules that can block production of the defective protein. Results are encouraging: two different and biologically active ribozymes can slow the rate of retinal degeneration in a transgenic rat model of the disease. The therapeutic applications of both of these approaches to the treatment of retinal degenerative diseases will continue to be explored.
The cornea is the transparent tissue at the front of the eye that serves two specialized functions. The cornea forms a protective physical barrier that shields the eye from the external environment. It also serves as the main refractive element of the eye, directing incoming light onto the lens. Refraction depends on the cornea acquiring transparency during development and maintaining this transparency throughout adult life. Corneal disease and injuries are the leading cause of visits to eyecare clinicians, and are some of the most painful ocular disorders. In addition, 60 percent of the American population have refractive errors that might be corrected to achieve sharp vision.
Corneal Gene Expression. A molecular analysis of developmental and cellular processes in the cornea has lagged behind that in other ocular tissues, largely from a lack of information about factors that control gene expression. However, progress has been made recently in studies of gene expression involved in the differentiation of the outer or epithelial layer of the cornea. First, at least two fibrous proteins known as keratins (K3 and K12) appear to be produced specifically in the corneal epithelium, and studies are underway to identify the factors that control the expression of their genes. Another opportunity to make significant research progress in the coming year comes from the high expression of certain enzymes in the corneal epithelial cells. The most highly studied abundant enzyme in the corneal epithelium of mammals is aldehyde dehydrogenase class 3 (ALDH3). It comprises up to 40 percent of the soluble corneal protein and can be induced by oxidative stress. Transketolase is another abundant corneal enzyme that is expressed in most other tissues at lower concentrations. Alpha-enolase is also found at unusually high concentrations in the cornea. This enzyme is of special interest because it is preferentially expressed in the cells in the outer margins of the cornea, where the stem cells reside. These findings have important implications for delivering gene therapy to the cornea that will be pursued during the next year.
Effective Treatment for Herpes of the Eye. An estimated 400,000 Americans have had some form of ocular infection with herpes simplex virus. This organism can produce a painful sore on the eyelid or surface of the eye and cause inflammation of the cornea. Less severe forms of ocular herpes include blepharitis, conjunctivitis, and epithelial keratitis, while the most severe outcome is stromal keratitis, which causes the body's immune system to attack and destroy an inner layer of the cornea. Recurring episodes of stromal keratitis can result in the need for corneal transplant. Once individuals develop ocular herpes, they have up to a 50 percent chance of a recurrence. This second flare-up could come weeks or even years after the initial disease. Each year, nearly 50,000 new and recurring cases are diagnosed in the United States, with stromal keratitis accounting for about 25 percent of the cases. Researchers and patients have long sought an effective means of preventing this disease or at least preventing the sight-threatening recurrence of the disease.
Since the late 1980s, the NEI has supported the Herpetic Eye Diseases Study (HEDS) as a means of determining the most effective treatments for this devastating disease. The Acyclovir Prevention Trial, a component of the HEDS, was a randomized, multi-centered clinical trial conducted in patients who had herpes of the eye during the preceding year, but did not currently have an active case of the disease. The subjects were assigned to either oral acyclovir or a placebo tablet. Researchers found that long-term treatment with oral acyclovir reduced by 41 percent the probability that any form of herpes of the eye would recur in patients who had the infection in the previous year. Importantly, researchers noted a 50 percent reduction in the rate of return of the more severe form of the disease-stromal keratitis. The study medication caused no serious side effects and there was no rebound in the development of herpes simplex virus in the six months after treatment with acyclovir was stopped. Researchers also found that oral acyclovir reduced the risk of herpes infections in other parts of the body, particularly the mouth and face, by 43 percent.
Corneal UV Filters. The high expression of enzymes in corneal epithelial cells is reminiscent of the recruitment of enzymes and stress proteins as refractive crystallins in the lens. In the lens, different enzymes are used as crystallins in different species. Similarly, the abundant enzymes in the corneal epithelium may differ among species. For example, ALDH3 is found in mammalian corneas but not in chicken or fish corneas. The unexpectedly high concentrations of these corneal enzymes suggest that they may play both enzymatic and nonenzymatic roles in the cornea. This is analogous to the situation in the lens, where the abundant crystallins have refractive and nonrefractive functions-a strategy called gene sharing. ALDH3 appears to protect the corneal epithelium against oxidative damage that could result from its continuous exposure to the environment. It has also been suggested that ALDH3 protects the cornea, as well as the rest of the eye, from oxidative stress by directly absorbing UV radiation. Indeed, since relatively few enzymes comprise the majority of the water-soluble proteins of the corneal epithelial cells, it has been proposed that they be collectively called "absorbins." Finally, it is even possible that, in addition to being UV filters, the abundant corneal enzymes contribute to transparency by minimizing protein concentration fluctuations and providing a continuous refractive index within the cytoplasm. The discovery of the possible multiple roles of the abundant corneal enzymes is an exciting area for future research and may offer more effective means of maintaining transparency of the cornea that is lost due to disease or injury.
Lens and Cataract
Cataract, an opacity of the lens of the eye, interferes with vision and is the leading cause of blindness in developing countries. In the U.S., cataract is also a major public health problem. Approximately 1.35 million cataract surgical procedures were performed on Medicare beneficiaries alone in 1991 costing approximately $3.4 million. Cataract surgery accounts for approximately 12 percent of the entire Medicare Part B budget and is the most commonly performed surgical procedure. The enormous economic burden of cataract will worsen significantly in coming decades as the American population ages. The major goals of this program, therefore, are to determine the causes and mechanisms of cataract formation, to search for ways to slow or prevent the progression of cataract, and to develop and evaluate new diagnostic and therapeutic techniques in cataract management.
Early Eye Development. Early development of the lens is controlled by specific genes that operate in a hierarchy of expression. The first of these genes to be identified was Pax-6. Mutations in Pax-6 are responsible for causing aniridia, a congenital malformation of the eye that results in cataract formation. Subsequent to this discovery, Pax-6 expression was found in other embryonic tissue including the tissues destined to form the nose, thus suggesting its more general involvement in craniofacial development. The significance of Pax-6 as a key developmental regulator has been substantiated in a number of experimental systems, most notably mouse and Drosophila, and its protein product is now characterized at the structural and functional levels. Researchers now view Pax-6 as a "master gene" controlling the expression of other genes during development. Recent studies have described a number of genes "downstream" of Pax-6 that may play significant roles in eye formation. As these genes and their products are characterized, the developmental hierarchy controlling ocular and more generally craniofacial development will be pieced together to form a picture of the developmental process and enhance our understanding of the molecular basis of congenital cataract.
Lens Cell Nutrition. The unique cellular structure of the lens requires a highly developed system for nutrition. The lens is a dense, compact structure containing two cell types: metabolically active epithelial cells and quiescent fiber cells. Unlike most other tissues, the lens is not nourished by its own blood supply and must take up nutrients from a circulating fluid called aqueous humor. Fiber cells are devoid of mitochondria and hence incapable of the energy-producing metabolism required for membrane transport. They are dependent on the outer epithelial cells to extract nutrients from the aqueous humor. Nutrients pass from epithelial cells to adjacent fiber cells and from superficial fiber cells to more internal fiber cells. The channels that allow direct communication and passage of nutrients between cells are called gap junctions. An extensive network of epithelial-fiber cell and fiber-fiber cell gap junctions are needed to maintain the health and transparency of the lens.
These gap junctions are formed by specialized proteins known as connexins. Genes encoding lens-specific connexins have now been cloned and the proteins they express characterized, allowing the construction of genetically modified mice with altered expression of gap junctions. Mice in which one of the fiber cell-specific connexins was deleted were found to develop cataracts. Detailed investigation of these mice revealed interesting physiological changes that were consistent with changes observed in human cataract. This evidence suggests that some forms of inherited cataracts are due to mutations in connexin genes. Additional studies of this mouse model of cataract may provide a better understanding of the role of gap junctions in normal physiological processes, as well as in the development of cataract.
Glaucoma is a group of eye disorders which share a distinct type of optic nerve damage that can lead to blindness. Elevated intraocular pressure is frequently, but not always, associated with glaucoma. Glaucoma is a major public health problem and the number one cause of blindness in African Americans. Approximately three million Americans have glaucoma, and as many as 120,000 are blind from this disease. Most of these cases can be attributed to primary open angle glaucoma, an age-related form of the disease. NEI activities in glaucoma research are directed toward understanding the mechanisms of the disease through basic research, identifying risk factors, and preventing blindness.
Racial Differences in Response to Glaucoma Treatments. Glaucoma is three to four times as common in blacks as in whites, and blindness from glaucoma is six times as common in blacks than in whites. In its early stages, glaucoma is usually treated with drugs in daily eye drops. In some patients, the beneficial effect of the eye drops lessens with time, and "advanced glaucoma" develops. Recent findings from the Advanced Glaucoma Intervention Study suggest that black and white patients with advanced glaucoma respond differently to two surgical treatments for the disease. Although both groups benefit from treatment, scientists found that blacks with advanced glaucoma benefit more from a regimen that begins with laser surgery, while whites benefit more from one that begins with an operation called a trabeculectomy.
Tissue Response to Intraocular Pressure Changes. Extramural and intramural scientists supported by the NEI have collaborated to develop a new method of studying human trabecular meshwork, the site of increased resistance to aqueous humor outflow in glaucoma. The system uses mechanical stress as a model for the distention of the trabecular meshwork that occurs with changes in intraocular pressure. These researchers found that the expression of a protein, myocilin, which has been shown to be linked genetically to some forms of glaucoma, is increased under certain experimental conditions. It is hoped that the use of this new experimental system to study human tissue will aid in the understanding of the changes that occur prior to the development of glaucoma.
Strabismus, Amblyopia, and Visual Processing
Developmental disorders such as strabismus (misalignment of the eyes) and amblyopia (commonly known as "lazy eye") affect 2-4 percent of the United States population. The correction of strabismus is a frequently-performed surgical procedure. In addition to research relevant to strabismus and amblyopia, the NEI supports investigations of the age-related inability of the lens to focus on nearby objects, irregular eye movements, and refractive errors. Three million Americans now have chronic visual conditions that are not correctable by eye glasses or contact lenses. Therefore, the NEI also supports research on improving the quality of life of persons with visual impairments by helping them maximize the use of remaining vision and by devising aids to assist those without useful vision.
Advances in Visual Imaging. The human and the monkey visual systems are remarkably similar. Scientists have learned a great deal about the human visual system by studying neural activity in the brains of alert, behaving monkeys. Our understanding of how we process visual information will increase significantly by recent advances in functional magnetic imaging (fMRI), a non-invasive method for peering inside the brain. Until recently researchers have been unable to use fMRI with monkeys because it has been difficult to train a monkey to sit still inside the noisy confines of a fMRI chamber. Two NEI grantees have overcome these challenges and published the first fMRI images of visual processing in the monkey brain. They used conventional fMRI machines to do this work, but development of a new generation of machines specifically designed for research in monkeys is underway. This advance will increase our fundamental understanding of fMRI images. For example, individual neurons can be studied in the monkey brain in visual centers that "light up" in both human and monkey fMRI images. Improvements in this approach during the next year will also help us understand what fMRI images tell us about the neuronal substrates in the brain that underlie a wide range of behavioral activities.
Guiding Neural Connections in the Visual System. As the human brain develops, billions of neurons form precise connections with each other. In the visual system, neurons in the eyes grow and connect to other neurons in the developing visual centers. Recent work demonstrates that electrical activity of these developing cells is essential for the correct neural wiring to occur. A special class of proteins called neurotrophic factors are necessary to stimulate the growth of neuronal processes, but understanding how these neurotrophic factors work together with electrical activity to sculpt the structure of the developing brain has been a mystery. NEI grantees have studied retinal ganglion cell neurons in culture, and shown that neurotrophic factors are unable to stimulate inactive neurons because the cell surfaces lack receptors for these factors. However, when these neurons are electrically active, receptors stored within the neuron are rapidly recruited and inserted at the cell surface. Neurotrophic factors bind to these receptors, which signal the neuron to grow processes. They also found that all neurons from the central nervous system (CNS) require electrical stimulation to respond to neurotrophic factors, but neurons in the peripheral nervous system do not. These observations may tell us not only how the developing brain molds its organization in response to experience, but also tell us that the inability of the CNS to regenerate connections following injury may depend on the presence or absence of electrical activity.
Story of Discovery
Visual Feedback During Early Life May Lead to Myopia.
Myopia or nearsightedness is a common condition in which images of distant objects are focused in front of, instead of on, the retina. This usually occurs because the eye is too long. Myopia occurs in approximately 25 percent of the population of the United States. More than 30 years ago, scientists found that raising a variety of animals with a closed eyelid led to the development of myopia, because the eye became elongated. Similar observations were made in human infants in which trauma or some other disorder resulted in neonatal eyelid closure. Over the next three decades a clearer picture of some of the processes involved in the control of refractive error in growing eyes has emerged.
A key advance has been the demonstration recently that in animals the growth of the eye and the development of accurate focus (refractive state) are guided by visual feedback during early life. Recent studies have shown that images not focused on the retina guide the developing eye to grow to correct for the lack of focus, and the focusing of images on the retina can cause changes in eye growth directly through signals from the retina to the outer coat of the eye. Evidence for this feedback mechanism has suggested new methods for the clinical treatment of myopia and other refractive disorders in humans that are now being tested in clinical trials. Additionally, recent observations have strengthened the association of increases in the amount of near work with increases in the rate of myopic progression in children, and have identified specific visual performance problems that put a child at high risk for the development of myopia.
Based on this information a clinical trial, the Correction of Myopia Evaluation Trial (COMET), is now being conducted to evaluate whether the use of special spectacle lenses known as progressive addition lenses (PALs) can slow the progression of juvenile-onset myopia as compared with single vision lenses. The PALs should provide clear visual input over a range of viewing distances without focusing effort by the child. The observation that the retina is involved directly in controlling eye growth has led to a search for molecules that may be involved in the signaling process. Currently, the best candidates are neurotransmitters that have already been shown to reduce experimentally-induced myopia in both birds and primates. These studies suggest the real possibility of effective approaches to prevent or slow down the progression of myopia.
National Eye Health Education Program
Low Vision Education Program. The NEI staff, through its National Eye Health Education Program (NEHEP), has begun the development of a new Low Vision Education Program. The primary target audience for this program is people age 65 and older with a visual impairment that interferes with daily activities. Focus groups were conducted across the country to learn more about the knowledge, attitudes, and practices of this target audience as they relate to how their visual impairment affects their lives and whether they know about and access services and devices available. Planning meetings were held with an ad hoc working group and NEHEP Partnership members to define program messages and strategies as well as to identify avenues to strengthen this public-private partnership. Based on recommendations from these groups, the following strategies will be utilized: 1) a broad-based consumer media campaign; 2) an education kit with resources for health care professionals, social service organizations, and other groups to use in educating the target audience; and 3) an outreach program, including traveling exhibits, for both the general public and health care and social service professionals that work with and serve older adults. NEI plans to launch this program in FY 2000.
Many of the following initiatives are part of broad-based initiatives that are trans-NIH in research scope and content and will be conducted in cooperation with other institutes. They are initiatives that will be pursued within the NIH areas of emphasis established by the NIH director in concert with the institute and center directors. The importance of these initiatives for vision research is highlighted below under the area of emphasis to which they refer.
Gene Expression in the Eye. The identification of important eye genes, their nucleotide sequence and patterns of expression would be a tremendous resource for vision scientists investigating the molecular mechanisms involved in visual system development and the genetic basis of blinding eye diseases. The success of this effort will depend on improving technologies for cloning and sequencing genes and for analyzing gene expression. DNA sequencing will focus on initially generating expressed sequence tags (ESTs). But, the ultimate goal will be to sequence full length cDNAs, which provide more comprehensive information on protein coding regions. Finally, the gene expression phase will involve high throughput methods for quantifying the expression of genes in microdissected tissue samples. This information about eye genes and gene expression in normal and diseased eye tissue will be made publicly available in an easily accessible format.
Functional Genomic Analysis of Mouse Models. Molecular and genetic analyses of mouse models have proven to be effective approaches to search for candidate genes for human ocular diseases and for understanding fundamental pathophysiological processes. For example, the cloning and characterization of the RDS/peripherin gene, responsible for retinal degeneration in the rds mouse, led to the identification of specific mutations in the homologous human gene that cause one form of retinitis pigmentosa. Other mutations in this gene cause human macular dystrophy. In addition, mouse models of cataract have been very successful in identifying genes responsible for cataract development and providing candidate genes for human congenital or age-related cataract. NEI proposes to accelerate the screening of mutant mice for interesting visual system phenotypes, and to characterize those mutants with the greatest potential for use in understanding molecular mechanisms of ocular development or eye diseases. The detailed molecular and physiological characterization of the mice with interesting ocular phenotypes would be supported through individual research grants and through the intramural research program.
Craniofacial Development. Advances on a number of fronts have opened new opportunities for furthering our understanding of craniofacial development. Progress in the Human Genome Project has allowed the identification of an ever increasing number of genes which when mutated result in developmental abnormalities affecting the craniofacial organs. Advances in mouse genomics have allowed scientists to investigate these genes in model systems. Opportunities to identify and characterize pathways in craniofacial formation have resulted from the mapping of genes causal for syndromic malformations. Some notable accomplishments include the identification of genes responsible for aniridia and Rieger's syndrome. On the horizon is a better understanding of X-linked cataract-dental syndrome, oculodentodigital dysplasia syndrome, and other developmental abnormalities.
New Approaches to Pathogenesis
Development of Cell and Tissue Resources for Transplantation in the Visual System. The visual system is ideally suited for cell transplantation and autoimmune research. The ease of anatomical examination and physiological studies of restored function offer investigators extraordinary experimental advantages. Cells of the retinal pigmented epithelium have been grafted into the subretinal space of eyes from rats with a retinal degenerative disease, prolonging the survival of photoreceptors. Transplanted fetal rat retinal cells grafted into the subretinal space in the eye of light-blinded rats develop, differentiate as photoreceptors, and form synaptic contacts.
This avenue of research will be expanded. The human corneal endothelium has no regenerative and only limited repair capability. When sufficient endothelial cell loss occurs, corneal edema and blindness ensue, with transplantation as the only available therapy. Progress is hampered by our ignorance of pathways to induce corneal endothelial cells to divide and repair. This initiative will support both cell culture and animal experiments, the use of growth factors, and molecular analysis of the cyclins and their associated kinases. Cell populations for corneal grafting also will be produced, and it may even be possible to program other cell types to acquire the properties of those of the cornea, thus providing a limitless source of cells for corneal reconstruction and replacement.
Bioengineering, Computers, and Advanced Instrumentation
Research Instrumentation. The NEI is cooperating with other institutes in supporting Bioengineering Science and Technology Partnerships. These awards will establish collaborative programs to create innovative and effective approaches to research instrumentation needs. Progress in the production of advanced vision research instrumentation requires multidisciplinary research teams that include bioengineers, basic scientists, and clinical scientists capable of supporting an integrative systems approach to this research. Vision Research -- A National Plan: 1999-2003 has identified many areas of vision research where advanced instrumentation needs are critical. These include the development of assistive devices for the visually impaired, imaging devices to improve non-invasive examination of ocular tissues for both research and disease diagnosis, instruments to analyze the biomechanics of the eye, and instruments to analyze visual performance, the further development of laser-targeted dye delivery systems which could revolutionize the visualization of blood vessels in the retina and the treatment of eye disorders; optical coherence tomography and confocal scanning laser polarimetry for quantitative measurements of the retinal nerve fiber layer; and the development very-high frequency ultrasound signal processing techniques to improve B-mode and spectral resolution.
New Avenues for the Development of Therapeutics
Peptidomimetics. Peptidomimetics are artificially-engineered small molecules that have biologic effects similar to that of macromolecules. The utilization of large proteins, such as monoclonal antibodies, for desirable binding and biological effects in the clinic has proven difficult. Typical problems include host immune response to the large molecule, poor cellular penetrance, and limited entry into specialized compartments of the body. An alternate approach is the synthesis of small peptides and organic mimetics derived from the structure of antibody complementarity-determining regions. These mimetics can then be screened for biologic activity. This approach has been used in the visual system to generate active mimetics of the tumor necrosis factor a (TNF-a) receptor and the CD4 anti-receptor antibody. TNF-a is a broadly active inflammatory mediator, and CD4 receptor interactions are required for T-cell activation. These mimetics are being studied as therapeutic interventions in animal model systems of T-cell dependent corneal inflammation and ocular uveitis.
Biology of Brain Disorders
Brain Imaging. The past 5 years have witnessed an impressive growth in the applicability of imaging technologies to the understanding of human brain function--and in visual function in particular. In the coming 5 years, developments in this area will provide new insight into the organization of brain areas involved in visual perception and in the control of visually guided behaviors. Because of its accessibility and large knowledge base, the visual system is already an important area of research in terms of imaging technologies and will undoubtedly continue to serve this role in the coming decades. In the realm of cortical processing, there is an urgent need to improve the resolving power of imaging techniques. While optical imaging of intrinsic signals in animals has resolution on the spatial scale of single functional units (e.g., orientation columns), less invasive techniques, such as functional magnetic resonance imaging (fMRI), which are much more suitable for use in humans, have not achieved comparable spatial resolution. Thus, an increase in spatial resolution of at least tenfold is required to extend the use of imaging technologies beyond localizing structures involved in various processes. In this case, the hurdles to be overcome are largely technical; attracting physicists, engineers, chemists, and investigators from other related disciplines will be necessary to overcome these technical obstacles. Considerably more work is also needed on understanding the relationship between functional MRI signals and neural activity.
Nerve Rescue and Regeneration. This field has witnessed explosive growth in the past 5 years, with one exciting discovery following another. For example, experiments in Drosophila, zebrafish, and mice have identified "master control" genes for eye formation. In humans, mutations of one of these genes account for a genetic disorder called aniridia, characterized by retinal, lens, and iris defects. Additional developmental studies have uncovered a specific class of factors that govern the expression of specific genes during development, thereby playing an essential role in establishing different classes of retinal ganglion cells. Proper myelination of the growing nerve appears to be ensured by a different traffic of chemical signals between growing retinal ganglion cells and oligodendrocytes, the cells that ultimately form the myelin sheath around the developing axon. Oligodendrocytes that fail to contact an unmyelinated axon undergo programmed cell death (apoptosis). Many of the genes that underlie this apoptotic "cell suicide" program have been identified and are expressed by most animal cells, including retinal ganglion cells. Survival of retinal neurons is promoted by a class of peptide trophic signals, including the recently discovered bcl-2, which inhibits activation of the cell suicide program. Overexpression of bcl-2 can rescue injured retinal ganglion cells from almost certain death. Finally, it has become possible in recent years to isolate developing retinal ganglion cells and grow them in tissue culture. This preparation has revealed that survival of retinal ganglion cells requires not only peptide factors such as the neurotrophins, but also intrinsic electrical activity. All of these exciting discoveries have critically important implications for the regeneration of damaged visual pathways, and therefore comprise a high priority area for future research under this initiative.
Because of its accessibility and its relevance to restoration of vision, the optic nerve, which consists of the axons of retinal ganglion cells, is an especially tractable and appropriate model system for the study of the molecular basis of regeneration. Restoring function to the visual system is also relatively easy to assess using electrophysiological, anatomical, and psychophysical techniques, and in many ways is less susceptible to the experimental limitations of other regeneration models such as the spinal cord. Nonetheless, it is almost certain that discoveries that reveal the molecular mechanisms mediating regeneration in the optic nerve will be of great importance elsewhere in CNS regeneration, particularly the spinal cord. Thus, special attention should be given to strategies that seek to identify the normal cues used to grow the optic nerve and to establish connections. These are likely to be useful in the context of regeneration. Additional effort will be invested in determining the molecular constraints in the adult nervous system that prevent axon growth and successful regeneration. The factors controlling neuronal growth are likely to be intimately involved in controlling the windows of critical time periods when the structure and function of the visual system can be altered by visual experience. Researchers still lack a compelling explanation for the factors that produce closure of critical periods. This has been due in part to the limitations of pharmacological approaches. Developing new model systems, such as visual plasticity in knockout mice, should provide a powerful new tool to approach this issue, especially if expression of relevant genes can be manipulated in space and time.
Innovations in Management and Administration
Vision Plan. In late spring 1998, the NEI and its advisory council, the National Advisory Eye Council (NAEC) published the sixth in their series of strategic plans, Vision Research-A National Plan: 1999-2003. In the development of this plan, panels of over 100 experts were assembled to represent each of the NEI's five formal programs--Retinal Diseases; Corneal Diseases; Lens and Cataract; Glaucoma; and Strabismus, Amblyopia, and Visual Processing--along with specialized groups representing Visual Impairment and Its Rehabilitation and Health Services Research. Information was also solicited for the panels through the NEI homepage (http://www.nei.nih.gov/). Visitors to the homepage were provided the opportunity to comment on the most significant accomplishments or advances since the last plan and recommend the most important vision research questions that should be addressed during the next 5 years. This information was then passed along to the panels for consideration in preparing their reports.
Each panel was asked to prepare a report that had the following elements: a program overview and goals; assessment of the progress within the program, particularly related to the goals and objectives in the last plan; program objectives that are the primary focus for research in the program; the research needs and opportunities that give rise to each objective; and strategic research questions that will lead to achievement of the goals and objectives.
The draft panel reports were reviewed by the National Advisory Eye Council (NAEC) at a special subcommittee meeting following the September NAEC meeting. The drafts that contained the comments and suggestions of NAEC members were then returned to the panels for their consideration. Final drafts were then sent to nearly 50 voluntary, advocacy, and scientific organizations that conduct and support vision research, as well as to the full Council, to solicit their views on the plan's final recommendations. Reviewers were asked specifically to consider whether any important areas of research or specific issues of importance to vision research had been overlooked. The result of this process is this strategic plan for vision research for fiscal years 1999 to 2003.
Information Technology. During the past year, the NEI established a new Information and Technology Management Branch within the NEI Office of Administrative Management. This action consolidated management and oversight of all NEI information technology resources at a high level within the Institute. This has brought about a significant improvement in the Institute's approach to a number of important information technology challenges, including the significant efforts required to make optimal use of the IMPAC II database and the implementation of effective Y2K compliance procedures.
NIH Budget Policy
The Fiscal Year 2000 budget request for the NEI is $395,935,000, excluding AIDS, an increase of $9,264,000 and 2.4 percent over the FY 1999 level. Included in this total is $5,250,000 for the following NIH Areas of Special Emphasis:
Biology of Brain Disorders
New Approaches to Pathogenesis
Genetics of Medicine
A five year history of FTEs and Funding Levels for NEI are shown in the graphs below:
NIH's highest priority is the funding of basic biomedical research through research project grants (RPGs). The emphasis on RPGs allows NIH to sustain the scientific momentum of investigator- initiated research while providing new research opportunities. NIH is committed to ensuring that the number of new investigators does not erode. In order to fund a maximum number of competing research project grants, the Fiscal Year 2000 request provides funds for competing RPGs at the same average cost level as Fiscal Year 1999. Noncompeting RPGs will not receive inflationary increases. The NEI will support 259 competing grants and 760 noncompeting grants, a decrease of 13 competing and an increase of 30 noncompeting grants, compared to FY 1999.
Promises for advancement in medical research are dependent on a continuing supply of new investigators with new ideas. In the Fiscal Year 2000 request, NEI will support 278 pre- and postdoctoral trainees in full-time training positions. Stipends will remain at the Fiscal Year 1999 levels.
Clinical research is a very high priority for the NEI, and is reflected in the Fiscal Year 2000 budget. Increased funding is proposed for both clinical research career development, clinical trials, and other applied clinical research. The NEI will fund 52 research career development awards in FY 2000, to sustain the pool of trained clinicians, epidemiologists, biostatisticians, translational basic scientists, and health service researchers. Among the new clinical trials is one that will be assessing the safety and effectiveness of laser treatment in preventing loss of vision among high-risk patients with age-related macular degeneration.
The Fiscal Year 2000 request includes funding for 35 research centers (core) grants, 205 other research grants, and 32 R&D contracts.
The mechanism distribution by dollars and percent change are displayed below: