News and Events

Congressional Justification for FY 2003

• Introduction
• Science Advances and Future Research Directions
• Health Disparities
• Healthy People 2010
• AIDS
• New Initiatives
• NEI Budget Policy

Authorizing Legislation: Section 301 of the Public Health Service Act, as amended. Reauthorizing legislation will be submitted.

Budget Authority:

This document provides justification for the Fiscal Year 2003 activities of the National Eye Institute (NEI), including HIV/AIDS activities. A more detailed description of NIH-wide Fiscal Year 2003 HIV/AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR).

The President's appropriations request of $631,818,000 for this account includes current law adjusted by assuming Congressional action on the proposed Managerial Flexibility Act of 2001.

Introduction

Congress created the NEI with the mission to conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of individuals who are blind. Inherent in this mission is clinical research across the spectrum of diseases of the eye and disorders of vision, as well as the investigation of the normal tissue and normal visual processes that will help gain a more complete understanding of the abnormal processes that lead to these conditions. These investigations are conducted in hundreds of extramural laboratories and clinics throughout the United States and in the NEI's own intramural facilities in Bethesda, Maryland. The highlights that follow are examples of the research progress that has been made with the investment of Federal funds in NEI-supported research and the direction that research will take over the next year.

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Providing Sight to Dogs Born Blind. The genetic disorder known as Leber's Congenital Amaurosis (LCA) is one of several incurable forms of blindness collectively known as retinitis pigmentosa. It was first described in 1869 by Theodor Leber, who studied this condition in children under the age of one year. No progress in understanding the cause of this childhood blindness was made for over 100 years. Currently, there is no treatment for LCA or related early onset retinal degenerative diseases. As a result of the Human Genome Project and the enormous progress made in the field of molecular genetics, there is now hope that the disease may be treatable soon.

Mutations in LCA account for about 11 percent of patients with early onset retinal degeneration. In 1994 NEI intramural scientists located an area on chromosome 1 that appeared to be involved in early retinal degeneration. This area on chromosome 1 contained a gene called RPE65. They also showed that the RPE65 gene product was located in the retinal pigment epithelium (RPE), a single layer of cells in close contact with the retinal photoreceptor outer segments. The function of the RPE65 protein was unknown, although it appeared to be involved in vitamin A metabolism in the retina. Assuming that a genetic defect in the RPE might cause an early retinal degeneration, the RPE65 gene was used to screen for mutations in patients with LCA. This resulted in the identification of mutations that cause LCA, when a child inherits two defective copies, one from each parent.

Research on the treatment of LCA has advanced enormously through recent studies of a naturally occurring congenital blindness in Swedish Briard dogs. In the course of long-term breeding by humans, these animals have acquired an RPE65 mutation that is identical to one that causes about 20% of the human LCA cases, although mutations in any of a dozen or so other genes are also known to cause LCA. Histopathology studies in homozygous dogs, which carry two defective copies of the gene, show abnormal rod photoreceptor cell morphology early in life, with slowly progressive photoreceptor degeneration and blindness.

Normal versions of the RPE65 gene were genetically engineered into an adeno-associated virus vector. Thousands of copies were directly injected behind the retina, close to the RPE cells, of the right eye of three blind Briards who were between the ages of two and four months old. Ninety-five days after injection, the animals had vision in the treated right eye, judged by pupil response, electroretinogram, and behavioral testing. Tissue from a subretinally injected eye demonstrated persistence of the transferred DNA. The left, control eye, of these animals remained blind. All three dogs were seeing well nine months after treatment, with no ill effects.

This study provides a "proof of concept" to show that gene therapy can restore vision in a large-animal model of a human retinal degeneration. Although previous studies had demonstrated that gene therapy could delay retinal degeneration, the present study demonstrates definitive recovery of function. The treated animals will continue to be studied in order to validate the effectiveness, during, and safety of the treatment. Future studies will include applying gene therapy to both eyes of a dog.

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Science Advances and Future Research Directions

Retinal Diseases
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 that process and transmit visual information via the optic nerve to the brain for further processing. 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, Usher's syndrome, ocular albinism, retinal detachment, uveitis (inflammation), and cancer (choroidal melanoma and retinoblastoma).

Treatment Reduces Vision Loss in Patients with Age-Related Macular Degeneration. Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the United States among persons over 65 years of age, the fastest growing segment of the US population. The condition affects the retina and leads to varying degrees of vision loss depending on the form and severity of the disease. The NEI sponsored Age-Related Eye Disease Study (AREDS) was designed to study of the clinical course of AMD and to evaluate the effects certain nutrients on the development and progression of this disease. The AREDS involved 4,757 participants, 55 to 80 years of age, in 11 clinical centers nationwide. Participants in the study were given one of four treatments: 1) zinc alone; 2) antioxidants alone; 3) a combination of antioxidants and zinc; and 4) placebo. Researchers conducting the study found that people at high risk of developing advanced stages of AMD lowered their risk of advanced development and its associated vision loss by about 25 percent, when treated with a high-dose combination of antioxidant vitamins C, E, and beta-carotene, and the trace element zinc. In the same high risk group, high doses of nutrients alone reduced the risk of vision loss caused by advanced AMD by about 19 percent. The demonstration that high levels of antioxidant nutrients and zinc significantly reduce the risk of advanced AMD and its associated vision loss is particularly important because these nutrients are the first effective treatment shown to slow the progression of this disease. This treatment plays a critical role in keeping people at high risk from progressing to the more advanced stages that result in serious loss of vision.

Collaborative Ocular Melanoma Trial. Choroidal melanoma is the most common primary eye cancer in adults. Enucleation or removal of the eye has been the standard treatment for choroidal melanoma for over a century, because the melanoma cells also can spread to other parts of the body and cause death. Radiation therapy emerged twenty years ago as a method to possibly preserve vision and reduce mortality. The Collaborative Ocular Melanoma Study (COMS) was supported by the NEI with significant co-funding from NCI to compare enucleation versus radiation with respect to survival. Investigators previously reported that patients with tumors large enough to require removal of the eye, who were randomized either to receive radiation treatment to the affected eye before it was removed or to having the eye removed without radiation treatment, showed similar 5 year survival rates of 60 percent. These researchers have recently reported that patients with medium-sized tumors, who were randomized either to receive radiation therapy or to have the eye removed, also had similar 5 year survival rates in the two groups of 82 percent. These results reveal that the size and location of the tumor is the most critical factor in influencing prognosis and emphasize the importance of early detection and treatment. With the data also showing similar survival rates for radiation therapy versus removal of the eye, quality of life issues become important factors in helping the patient and doctor determine treatment options.

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Potential Gene Therapy for Dominantly-Inherited Retinal Diseases. Retinal diseases offer promising targets for gene therapy, since over 100 different genes are known to be involved in causing retinal disorders. In some inherited diseases, only one of the pair of corresponding genes normally found on a chromosome (one gene on each strand of the DNA) need be mutated to cause the disease. These are called dominantly-inherited diseases. One approach to curing certain dominantly-inherited disorders is to deactivate the mutated gene, leaving the corresponding normal gene partner intact and functional. Normally during gene expression, a messenger RNA (mRNA) molecule is produced that can be read within the cell and ultimately directs the assembly of a gene product. A similar approach is being explored using ribozyme therapy. Ribozymes are small RNA molecules, which act like scissors to cut the mRNA produced from the mutated gene leaving the mRNA from the normal gene intact. Recent experiments in animals have demonstrated that it is possible to deliver ribozymes to photoreceptors cells and decrease the number of mutant mRNA molecules made from a known dominant mutation in the rhodopsin gene. This treatment effectively cured the retinal degeneration for up to eight months. The ribozyme therapy was also effective when administered at a late stage of the disease. Demonstration of a long-lasting therapeutic effect that can be instituted at late stages of the disease is of particular importance in human retinal degenerations, because so many have a late onset. Research will continue into the application of this therapy to other dominantly-inherited, single-gene mutations that cause retinal degenerations.

Discovery of Gene for Hallervorden-Spatz Syndrome. Hallervorden-Spatz syndrome (HSS) is a rare, inherited, neurological disorder associated with high accumulations of iron in the brain, and causes progressive degeneration of the retina and nervous system. In addition to a number of neurological symptoms that develop during childhood, some patients also develop degeneration of the retina. Death usually occurs in early adulthood, approximately 10 years after onset. Scientists recently discovered a defective gene that produces an ineffective enzyme in patients with HSS. The enzyme is needed by the body to use vitamin B5, which is required to produce some of the body's essential compounds. These researchers hypothesize that the production of the ineffective enzyme by the defective gene causes blockage of normal metabolism and the accumulation of metabolic materials resulting from that blockage. It is believed that this accumulation results in degeneration of the retina and high concentration of iron in the neural tissues. Research is now being focused on developing treatment strategies that bypass this defective enzyme, allowing the body to use vitamin B5 to help make essential components. Understanding the biochemical defects in HSS may also provide insights into the effect iron has on other neurodegenerative diseases associated with high iron accumulations, such as Parkinson's disease.

Gene Regulation in the Retina. The eye is amenable to treatment with gene therapy. The eye and its tissues are easily accessible for viral vector or drug delivery, and it is an immunologically-privileged site, i.e., it is not subjected to the full range of the body's immune responses. Current research is directed toward using viral vectors or vehicles to transfer normal genes into cells that have defective or missing genes. However, in order for gene therapy to live up to its full potential, it is necessary to develop the means to regulate gene expression by externally turning on and turning off gene expression, perhaps with an active compound that can be taken orally. NEI-supported scientists have used a portion of a bacterial gene (called Tet-On) to control expression of genes transferred to the retina. These scientists used viral vectors to carry the Tet-On activator and a fluorescent pigment that could be easily detected when produced, linked to the appropriate tetracycline response element. After administration of an agent to turn on the gene, the researchers found that the fluorescent pigment was detectable in the target retinal tissues. Using this same system, they were also able to transfer a human growth hormone gene and regulate the production of growth hormone. Continuation of research on this system offers a promising means of delivering replacement genes for those found to be defective or missing, while regulating the expression of those genes or the product of that expression. It opens the possibility of delivering the genes necessary to ameliorate a variety of eye diseases and being able to control them as needed in a similar way to the therapeutic application of conventional drugs.

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Potential Treatment for Neovascularization Due To Age-Related Macular Degeneration. The abnormal growth or proliferation of blood vessels is a process known as neovascularization. A number of diseases involve neovascularization, including the growth of some tumors, arthritis, and a variety of eye diseases. In the eye neovascularization can have a devastating impact on vision, particularly in diseases like age-related macular degeneration (AMD). Several proteins or drugs have been found to inhibit or stimulate the neovascular process. One such promising protein is endostatin, a potent inhibitor of blood vessel growth (angiogenesis) in tumors. In order test the effects of endostatin on ocular neovascularization, NEI-sponsored researchers developed a viral vector to transfer the gene sequence for endostatin coupled with a sequence that creates a signal that can be detected to ensure the endostatin gene has been successfully transferred. They injected this vector system into the bloodstream of an animal model prior to inducing neovascularization by laser treatment. These scientists found that the endostatin gene transfer successfully sustained high levels of endostatin that prevented choroidal neovascularization in the animal model. Further study of endostatin's prevention of intraocular neovascularization may help determine whether it is useful in causing regression of neovascularization that is caused by AMD or other related eye diseases.

Another promising avenue of investigation involves vascular endothelial growth factor (VEGF), which has been shown to play a major role in stimulating the formation of new blood vessels in the retina. But the role of VEGF in choroidal neovascularization (CNV), which occurs in some forms of AMD, is less clear. Recent studies by other NEI-supported scientists in a mouse model of CNV have demonstrated that inhibiting certain properties or activities of the VEGF receptor protein results in almost complete inhibition of CNV. The identification of molecular factors involved in a pathologic process such as ocular neovascularization makes it possible to design effective new drug treatments.

Speed of Light Responses. A single photon of light can activate a single molecule of the visual pigment rhodopsin in a rod photoreceptor cell outer segment, initiating the process of vision or phototransduction. To maintain a high sensitivity to light, rod cells maintain an enormous number of rhodopsin molecules (about one billion) in their light-capturing outer segments. Although this number maximizes rod cell sensitivity, the rod cell light response rate is relatively slow. Recently, NEI-sponsored scientists have created transgenic mice in which one of the pair of rhodopsin genes has been deleted. These animals show a 50 percent reduction in the levels of rhodopsin, but a faster recovery to a flash of light. This suggests that the extremely high packing density of rhodopsin that maximizes sensitivity, also sacrifices speed in the response to light. Rhodopsin density may limit other steps in the phototransduction process as well. Achieving a better understanding of the phototransduction process may help understand how the process is impaired in a variety of retinal diseases and suggest the means to ameliorate that impairment.

Corneal Diseases
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, approximately 25 percent of the American population have a refractive error known as myopia or nearsightedness that requires correction to achieve sharp vision¹; many others are far-sighted or have astigmatism.

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Spread of Ocular Herpes Simplex Virus Infection. Herpes Simplex Virus (HSV) is the leading cause of blindness due to an infectious pathogen in the US. Repeated cycles of latency (in which the virus is dormant) and reactivation can lead to progressive scarring and clouding of the cornea that, in turn, leads to blindness. Corneal infection is accompanied by periocular disease (spread of virus to the eyelids and conjunctiva) in over 50 percent of the acute infections. In order to determine whether these tissues are infected directly during the initial (primary) corneal infection, or are infected by newly formed virus in the nervous system, NEI-sponsored scientists employed new molecular genetic techniques to monitor and quantify the appearance of viral gene products in an animal model of HSV ocular infection. This permitted tracking the time course of infection in cornea, the nervous system (trigeminal ganglia where the latent virus resides), and the surrounding ocular (periocular) tissues. The time course suggested that after HSV infects the cornea, the virus travels to the nerve cells in the trigeminal ganglia and after residing and quickly replicating in the nervous system, to the periocular tissues. Similarly, human spread of virus has a time course that closely mimics that observed in the animal model. This research suggests that in future treatment studies of acute, primary infection of the cornea, topical antivirals may be insufficient to limit disease, and rapid systemic treatment may be the best means of preventing spread of infection to these tissues.

Suppression of Specific Molecular Targets Improves The Success Rate of Corneal Transplants. Although most corneal transplants are successful, approximately 20 percent fail due to immunologic rejection of donor tissue. Evidence is accumulating that host tissues at the transplant site increase the concentration of certain molecules that are responsible for recruiting the immune and inflammatory cells that cause rejection. Specific inhibitors of these molecules can be used therapeutically to suppress the immune response and ultimately lead to greater success of grafts.

Protein Involved in Cell Migration May Inhibit Tumor Growth. The outermost tissue in the visual system is the corneal epithelium. If the integrity of this epithelium is compromised by trauma, such as mechanical abrasion or chemical burn, the epithelium rapidly is activated to increase cell number (proliferation) and slide over the damaged area (migration) to close the wound and re-establish the barrier function. Scientists have identified a number of biochemical components that contribute to the wound healing process. Recently, NEI-supported investigators found that a cell protein called pinin is able to modify a small number of genes involved with corneal cell motility and proliferation. They found that cell motility genes were stimulated and cell proliferation and migration genes were inhibited by pinin. Since pinin increases cell adhesion and limits migration, it may be possible to enhance wound healing by inhibiting pinin's action. Alternatively, stimulation of pinin expression may play a role in suppression of tumors that develop due to abnormalities in cell adhesion pathways. Additional research may help identify the key molecules associated with these pathways and may lead to treatments that enhance wound closure and more rapidly restore the epithelial barrier.

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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. 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.

Long-term Estrogen Replacement Therapy Reduces the Risk of Cataracts. Because cataracts are a major cause of visual impairment, cataract surgery is one of the most frequently performed surgical procedures in the United States. NEI-supported researchers have found that postmenopausal women on estrogen replacement therapy are less likely to develop cataracts. Women and their doctors should take this potential benefit into consideration when discussing whether or not estrogen replacement therapy is appropriate for them.

Protection of the Lens by A-Crystallin. Lens transparency requires high concentrations of protein within specialized lens fiber cells. Because fiber cell proteins are not removed or replaced during the life of an individual, the lens is especially susceptible to aging effects. As these proteins age, changes occur that cause them to aggregate into large, opaque structures that can interfere with vision. To maintain transparency, the lens must maintain the integrity of its proteins. In general, cells use a chaperone protein to protect other proteins when the cell is subjected to stress. In the lens, -crystallin, a protein belonging to a family of chaperones, is composed of two subunits that also function as chaperones. Further investigation of the protective roles of these subunits in epithelial cells led scientists to test their ability to protect human epithelial cells from apoptosis (programmed cell death). They found that the subunit A-crystallin protected the cells from a variety substances that are known to cause apoptotic cell death. They also found that A-crystallin is two to three times more effective than the other subunit in protecting animal lens epithelial cells grown in the laboratory from stress-induced cell death. Continuation of this line of investigation will aid in understanding the range of protective mechanisms available to the lens may assist in determining the events that overwhelm them and lead to formation of cataract.

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Lens Cell Survival. The lens is a dense, compact structure containing two cell types: epithelial cells and fiber cells. Fiber cells are terminally differentiated, which means they have lost their ability to synthesize new proteins. Therefore, the lens is dependent on a thin layer of metabolically active epithelial cells for its health and survival. This is particularly important, because lens cells survive for the life of the individual. Until recently, factors that maintain lens cell survival have not been understood. A recent report by NEI-sponsored researchers has characterized one factor called LEDGF (lens epithelium-derived growth factor) that stimulates the synthesis of specific stress response proteins. LEDGF appears to have the ability to promote the survival of a wide range of cells. In a second study, these scientists used LEDGF to rescue degenerating photoreceptors in rat models of retinal degeneration. Data from this study suggested that such rescue is effected through stress-related protection. These findings open the possibility that this factor could have far reaching therapeutic potential for ocular diseases caused or exacerbated by environmental stresses.

Imaging the Human Lens. Conventional magnetic resonance imaging (MRI) is a sensitive diagnostic imaging tool that provides three dimensional images of the body's interior without the use of radiation. A refinement of MRI, called magnetization transfer contrast (MTC) enhancement, has been shown to be sensitive to the accumulation of fluid in tissues (edema) that changes the concentration, movement, and structure of large molecules within those tissues. NEI-supported researchers attempted to determine the feasibility of creating high resolution MTC-enhanced images of human eyes. These scientists were able to obtain high resolution images of the fine structures surrounding and within the eye with minimal distortion with standard and MTC-enhanced MRI, in spite of the motion of the eye and eyelids and the bony structures surrounding the eye. Interestingly, they found that MTC-enhanced MRI was better able to detect nuclear cataract (opacities in the center of the lens) and standard MRI was better at detecting cortical cataract (opacities in the outer areas of the lens). Because MTC-enhanced MRI provides the means to detect subtle changes in the molecular structures of the eye non-invasively, it has important implications for further study of changes within the lens that occur prior to development of an opacity and for monitoring the effectiveness of efforts to halt or reverse cataractous changes.

Glaucoma
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 glaucoma², with about half of these unaware that they have the disease. As many as 120,000 are blind from this disease³. 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.

A Protein Associated with Atherosclerosis May Give New Insights into Glaucoma. The precise cause of this increase in pressure in the eye in glaucoma is not known. Considerable evidence points to a blockage at the site from which fluid flows out of the eye as the cause of pressure elevation. NEI-supported scientists have identified a molecular marker of glaucoma in the trabecular meshwork endothelial cells, specialized cells within the tissue that regulates the exit of fluid from the eye. The marker, ELAM-1 (endothelial leukocyte-adhesion molecule-1), is also the earliest marker for the build up of fatty deposits, known as atherosclerotic plaques, in the linings of blood vessels damaged by high blood pressure or other factors. These scientists detected this molecule in eyes from glaucoma patients but not in eyes from normal controls. Further study revealed that two other molecules commonly associated with oxidative stress and inflammatory reactions were found only in glaucomatous endothelial cells. The investigators speculate that oxidative damage to the trabecular meshwork cells initiates a self-sustaining signaling pathway intended to protect cells, but that its prolonged activation may initiate glaucomatous damage. Further investigation of this pathway may offer fresh insights on the disease state and new intervention points for therapy.

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Myocilin in Aqueous Humor. NEI-supported scientists have located a mutation in a gene on chromosome 1 that is linked to the most common form of glaucoma, primary open angle glaucoma. This gene directs production of myocilin, a protein found in the trabecular meshwork. It is also found in other eye tissues, but researchers wanted to know whether myocilin was also present in the aqueous humor, the fluid responsible for the build up of pressure within the eye. They analyzed the aqueous humor from human, monkey, and cow eyes and found that myocilin was a component of the aqueous humor in each. They found that the protein was larger than expected and was hydrophobic or unable to mix with water. The scientists also found that the proteins became tightly adherent to filters that become obstructed when aqueous humor was passed through them. Myocilin's relatively large size may indicate that it contains repeating units or be in association with other proteins that are present in the aqueous humor, and the suggestion that myocilin may be involved in the obstruction of filters of the size of the tissues involved in aqueous humor outflow from the eye are intriguing and warrant additional study.

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 population⁴, ⁵. The correction of strabismus is one of the most 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 lenses⁶. 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.

Bringing Sleep into Focus. Recent research on the developing visual system in animals has provided direct evidence that sleep in early life plays a crucial role in brain development. In normal animals the numbers of cortical neurons dominated by inputs from each eye are roughly equivalent. Neurons receiving input from the same eye are grouped in aggregates in the visual cortex called ocular dominance columns. NEI-sponsored researchers used monocular deprivation (MD), i.e., temporarily blocking the visual input to one eye, followed by periods of sleep or wakefulness to develop an assay for the effects of sleep on neural plasticity. They found that sleep enhanced the effects of MD on visual cortical responses, but wakefulness, even in complete darkness, did not do so. The researchers theorized that sleep is a period of low sensory input during which the brain consolidates events of recently acquired tasks and that during development, sleep allows the consolidation of changes in ocular dominance evoked by short-term visual experience. Sleep deprivation prevents consolidation of the visual experience and appears to allow accumulated changes to reverse. The results provide the first direct evidence that sleep and sleep deprivation modify experience-dependent changes in the brain, and also suggest that synaptic circuits are modified during sleep. Additional research exploring the mechanisms underlying sleep and may provide a clearer understanding of the function of sleep.

The Timing of Visual Responses to Light. The ability to perceive changes in a visual scene requires that the visual system be able to detect or resolve the changes in both space and time. Therefore, one of the main functions of the retina is to separate visual information into these spatial and temporal components. Retinal photoreceptor cells, which capture light, are physically separated within the retina, and this separation accounts for considerable spatial resolution. However, photoreceptor light responses are uniform in their time course; and only a single neurotransmitter substance, glutamate, appears to be released by photoreceptors. Thus, temporal resolution must occur somewhere else within the millions of neurons in the retina and brain that comprise the visual system. Several different types of specialized neurons called bipolar cell are known to receive neural impulses from the photoreceptors. Scientists attempted to determine where temporal resolution occurred by making measurements of electrical activity inside of single, distinct types of bipolar cell and found that each distinct type of neuron uses a different and distinct receptor subtype to bind the glutamate released by the photoreceptors. Each glutamate receptor subtype responds with a different and unique time course, shaping the bipolar cell's subsequent response to glutamate released by the photoreceptors. Thus, diverse glutamate receptor subtypes with different functional properties begin the process of temporal resolution at the visual system's first synapse, the point at which neural impulses are passed between neurons. Additional research may help determine whether different glutamate receptor subtypes are associated with different morphological types of synapses at photoreceptors.

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Early Eye Development. Development of the vertebrate eye is controlled by specific genes that operate in a hierarchy of expression. Some of these genes have been identified as "master controls". In Drosophila, the fruit fly, loss of any one master control gene results in the failure to form an eye, while the misexpression of any one is sufficient to form an eye in aberrant body locations. One of these Drosophila master genes, called eyeless, is similar to a human gene, Pax-6. Pax-6 mutations result in aniridia, a congenital malformation of the eye associated with improper development of the iris and with the formation of cataracts. Pax-6/eyeless genes are found in other embryonic tissues, and they are crucial to the formation of other organ systems, such as the nose or antenna. In an effort to understand the function of master genes and the factors, which turn on each tissue-specific developmental program, NEI supported scientists recently identified two signaling pathway receptors in Drosophila that act before the eyeless gene to specify eye formation. One is the transmembrane receptor, Notch that promotes eye formation. The second is the EGF receptor that blocks eye formation in favor of antennae. These findings are the first to suggest a mechanism of global control of eye development. Continuation of this line of research is essential to the understanding of the developmental hierarchy controlling ocular development and will enhance our understanding of the molecular basis of congenital diseases of the eye.

Health Disparities

Diabetic Retinopathy in the Mexican-American Population. Mexican-Americans are known to have a high rate of diabetes along with more severe hyperglycemia, which indicates poor glucose control. This can lead to major complications of diabetes, including severe diabetic retinopathy and blindness. As a means of determining the causes and prevalence of blindness and visual impairment in the U.S. Mexican-American population, the NEI supported the study Proyecto VER (Vision Evaluation and Research). This study assessed visual impairment in a population-based sample of 4500 Mexican-Americans age 40 or older, residing in Tucson and Nogales, Arizona. The rate of diabetes in this group was 20 percent, twice the rate reported for non-Hispanic Whites. The rate of diabetic retinopathy in those with diabetes was 48 percent, a rate similar to that of non-Hispanic Whites. Importantly, 15 percent of study participants did not realize they had diabetes and were newly diagnosed by the study. Among this group of newly diagnosed diabetics, 23 percent had early to moderate diabetic retinopathy, a potentially blinding eye complication of diabetes. Another nine percent had advanced diabetic retinopathy and were in immediate danger of losing some vision. This study points to the importance of early diagnosis and treatment of diabetes and the importance of regular, dilated eye exams in this high-risk, minority population and underscores the need for the NEI's National Eye Health Education Program to continue targeted health education activities and messages directed to addressing these concerns.

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Healthy People 2010

Baseline Estimates of Visual Impairment. The NEI is conducting two projects in support of the vision objectives in Healthy People 2010 that will help determine baseline levels of the extent of the problem of eye diseases. A meta-analysis of prevalence data on diabetic retinopathy, glaucoma, cataract, macular degeneration, and refractive errors is currently underway. This analysis is based on a review of major population-based studies that report prevalence rates for vision-related impairments. This analysis should be completed in early 2002. In addition, the NEI is supporting a vision supplement on the Federal government's National Health Interview Survey and several vision-related questions on the National Health and Nutrition Examination Survey (NHANES). Data from these two surveys will also provide baseline data on race and ethnicity, gender, family income level, and disability status. Data will be available in 2003. Healthy People 2010 data will also be used by the NEI's National Eye Health Program to determine opportunities for strategic eye health education programs in select populations, including older adults.

AIDS

Inhibition of CMV Replication. Cytomegalovirus (CMV) is a common herpes virus that usually causes subclinical or mild infection in adults with healthy immune systems. In immunocompromised people, such as AIDS patients or organ transplant recipients, the virus can cause CMV retinitis, leading to pain and a loss of vision. The inflammatory response itself can cause a decrease in vision. One new therapy involves antisense oligonucleotides, compounds that block the production of viral proteins within cells by interfering with the messages directing their production. NEI-sponsored researchers have used two model systems for growing cells in the laboratory for testing two oligonucleotides that have been developed against CMV. One system employs human fibroblasts (skin cells) and the other human retinal pigment epithelial (HRPE) cells, derived from a layer of cells in close contact to the retinal photoreceptors. The researchers found that both oligonucleotides were effective in inhibiting viral damage to the cells. These scientists found the oligonucleotides were effective up to 6 days after introduction of the virus in HRPE system but only up to 3 days in the fibroblast system, suggesting that this may be due to the slow spread of the virus through the HRPE cells, as is seen in patients with CMV retinitis, compared to a more rapid spread in fibroblasts. This research also suggests that the HRPE system may be an appropriate system for testing other antiviral therapies.

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New Initiatives

Ocular Complications of Diabetes. The NEI will support several initiatives that were among the recommendations of the Congressionally-established Diabetes Research Working Group. One initiative will accelerate the evaluation of new treatments for diabetic macular edema through development of a multicenter clinical trials network that will include a Network Study Chair, a Coordinating Center, a Fundus Photograph Reading Center, and a number of participating clinical centers. Macular edema secondary to diabetic retinopathy is a major cause of visual loss in patients with diabetes and occurs when damaged retinal blood vessels leak fluid and lipids (fats) that cause swelling of the macula and blurring of vision. NEI plans to support this network approach to provide a framework for more rapid initiation of important studies, efficient use of pooled clinical expertise in idea generation and protocol development, and efficient use of central resources for data management, quality control, and outcome evaluation.

Glaucoma - A Neurodegenerative Disease. Glaucoma is a heterogeneous group of disorders that share a distinct type of optic nerve damage that can lead to blindness caused by the death of retinal ganglion cells. NEI is planning an initiative on neurodegeneration/neuroprotection that will build on the discovery that retinal ganglion cells die by apoptosis (programmed cell death) following exposure to elevated intraocular pressure or other insults. Retinal ganglion cells are sensitive to the neurotransmitter glutamate and other mediators of neuronal death, as well as to certain growth factors and internal mechanisms that are known to enhance the survival of these neurons. Initial clinical studies of neuroprotective agents are underway. A better understanding of glaucoma as a neurodegenerative disease will lead to a better means to prevent or delay the death of retinal ganglion cells and to promote their survival.

Cell and Tissue Engineering Approaches to Corneal Disease. Recent studies have demonstrated that the corneal epithelial stem cells necessary for normal regeneration reside in the limbus, the narrow peripheral zone of cornea bordering the conjunctiva. These stem cells are postulated to be the progenitor cells necessary for maintaining the normal corneal epithelium. Initial clinical results with limbal transplantation in patients with severely damaged corneas have been promising, and this new field deserves expanded emphasis. The NEI will launch an initiative to better understand the biology and function of corneal stem cells, to identify molecules that regulate the growth and differentiation of corneal epithelial cells, to explore tissue engineering approaches (artificial cornea), and to determine the role of corneal nerves in the regenerative process.

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Genomics and Proteomics. NEI will expand its efforts to introduce innovative technologies and to upgrade vision research facilities. This will include updating protein sequencing technology, enhancing bioinformatics capacity, introducing state of the art imaging technology, upgrading proteomics tools, and establishing transgenic mouse facilities. The newly-established NEIBank website already includes data for a number of human eye cDNA libraries. The NEIBank will be greatly expanded to include expressed gene sequences from other sources and other species. It will also include links to resources on protein structure, proteomics, micro-arrays and other topics. This expansion will significantly advance research efforts to identify and sequence genes that are expressed in the visual system. The identification of important genes, their nucleotide sequence and patterns of expression will be a tremendous resource for vision scientists investigating the molecular mechanisms involved in visual system development and the genetic basis of blinding eye diseases.

Gene-Transfer and Gene-Based Approaches to Neurodegeneration. Neuronal cell dysfunction and degeneration are hallmarks of a number of important eye diseases including retinitis pigmentosa, age-related macular degeneration, and glaucoma. NEI will expand its support of collaborative multidisciplinary research focused on the development of novel therapies, such as gene transfer or other gene-based or pharmacological approaches, to restore or prevent the loss of neuronal function due to these diseases. The rapid and efficient translation of laboratory research findings into clinical application requires a comprehensive and highly integrated approach. The initiative will make resources, including shared access to services and facilities, available to scientists from several disciplines to form research teams to address scientific and technical questions that would be beyond the capabilities of any one research group.

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NEI Budget Policy

The Fiscal Year 2003 budget request for the NEI is $631,818,000, including AIDS, an increase of $48,955,000 and 8.4 percent over the FY 2002 level.

A 5 year history of FTEs and Funding Levels for NEI are shown in the graphs below. Note that Fiscal Years 2000 and 1999 are not comparable for the Managerial Flexibility Act of 2001 legislative proposal.

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One of NIH's highest priorities is the funding of medical research through research project grants (RPGs). Support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while providing new research opportunities. The Fiscal Year 2003 request provides average cost increases for competing RPGs equal to the Biomedical Research and Development Price Index (BRDPI), estimated at 4 percent. Noncompeting RPGs will be funded at committed levels which include increases of 3 percent on average for recurring direct costs.

Future promises for advancement in medical research rest in part with new investigators with new ideas. In the Fiscal Year 2003 request, NEI will support 267 pre- and postdoctoral trainees in full-time training positions, the same number as in FY 2002. Stipend levels for NRSA trainees will increase by 4 percent over Fiscal Year 2002 levels.

The Fiscal Year 2003 request includes funding for 40 research centers, 210 other research grants, including 55 clinical career awards, and 51 R&D contracts. The R&D contracts mechanism also includes support for 8 contracts for the Extramural Clinical and Pediatric Loan Repayment Programs. Intramural Research and Research Management and Support receive increases of 9 percent over FY 2002.

The FY 2003 budget request includes additional funding targeted to support diabetes research. This will enable the NEI to fund more grants pertaining to diabetic retinopathy, specifically ones that will improve our ability to predict risk, make early diagnoses, and to assess progression of the disease. The money will also accelerate the evaluation of new treatments for diabetic macular edema.

The mechanism distribution by dollars and percent change are displayed below:

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¹Sperduto R, Seigel D, Roberts J, Rowland M: Prevalence of myopia in the United States. Arch Ophthalmol 101(3):405-407, 1983.

²Rahmani B, Tielsch J, Katz J, et al: The cause-specific prevalence of visual impairment in an urban population, the Baltimore Eye Survey. Ophthalmology 103(11): 1721-1726, 1996.

³Kahn HA and Moorhead HB: Statistics on blindness in the model reporting area, 1969-1970. U.S. Department of Health, Education, and Welfare. Public Health Service. Publication No. (NIH)73-427. pp. 120-143.

⁴ Hillis A, et al: The evolving concept of amblyopia: a challenge to epidemiologists. Am J Epidemiol 118(2):192-205, 1983.

⁵Preslan M, Novak A: Baltimore Vision Screening Project. Ophthalmology 103(1):105-109, 1996.

⁶Tielsch J, Sommer A, Will K, Katz J, Royall R: Blindness and visual impairment in an American Urban population, the Baltimore Eye Survey. Archives of Ophthalmology 108:286-290, 1990.