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Congressional Justification for FY 2004

National Eye Institute

Authorizing Legislation:
Section 301 of the Public Health Service Act, as amended.

FY2002 Actual FY2003 Amended President's Budget FY2004 Estimate Increase or Decrease
FTEs BA FTEs BA FTEs BA FTEs BA
233 $579,540,000 229 $625,076,000 225 $648,229,000 (4) $23,223,000
Reauthorizing legislation will be submitted.

Budget Authority:
This document provides justification for the Fiscal Year 2004 activities of the National Eye Institute (NEI), including HIV/AIDS activities. A more detailed description of NIH-wide Fiscal Year 2004 HIV/AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR).

Introduction

Congress created the National Eye Institute (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 visually impaired. 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.

Story of Discovery

New Treatments for Diabetic Retinopathy and Age-Related Macular Degeneration. The formation of new blood vessels, or angiogenesis, within the eye is a fundamental process that occurs in normal development and in a wide range of eye diseases and other disease processes. Proliferation of new blood vessels, or neovascularization, also occurs as the dominant feature in many blinding eye diseases: proliferative diabetic retinopathy (PDR), age-related macular degeneration (AMD), certain kinds of glaucoma, and retinopathy of prematurity (ROP). While inhibition of abnormal new vessel growth does not necessarily cure the underlying disease, it can preserve vision by preventing complications associated with neovascularization, such as hemorrhage and edema.

The molecular understanding of events involved in the process of angiogenesis has advanced significantly since the purification of the first angiogenic molecules nearly two decades ago. In1980 an aqueous extract of mammalian retinas showed the presence a vascular cell proliferative factor, later identified as basic fibroblast growth factor (bFGF). In the mid 1990s investigators discovered that a specific molecule, vascular endothelial growth factor or VEGF, appeared to have angiogenic activity and also controlled the passage of substances into and out of blood vessels. Although originally studied for its role in tumor development, it received considerable attention, because it seemed to account for the association between neovascular disease of the retina and increased vasopermeability. Patients with diabetic retinopathy showed a clear correlation between the extent of their disease and the levels of VEGF in their eyes.

Over the past decade researchers have discovered that angiogenesis can be turned on or suppressed by a number of other molecules. These discoveries have helped in the development of therapies for abnormal retinal angiogenesis to prevent people from going blind from vascular proliferative diseases. Clinical trials are currently underway to test the efficacy of some of these therapies in preventing the progression of diabetic retinopathy and neovascular AMD. Among the newest inhibitors of angiogenesis is an enzyme involved in protein synthesis, tryptophanyl-tRNA synthetase (TrpRS). One form of this enzyme has been shown to inhibit growth and migration of blood vessel cells that were exposed to agents that induce angiogenesis and may also inhibit the growth of new blood vessels in animal eyes and tumors.

Other new approaches to controlling angiogenesis are also being explored. Adult bone marrow-derived stem cells have been found to seek out and become incorporated into newly forming blood vessels of the retina. One class of these stems cells contains endothelial precursors cells (EPCs) that can form blood vessels. When these EPCs are injected into a mouse with a retinal degeneration whose vasculature normally degenerates with age, they rescue and maintain a normal vasculature. Because the EPCs target the retinal vasculature, scientists were able to incorporate TrpRS into the cells and demonstrate inhibition of normal mouse blood vessel development, demonstrating their therapeutic potential. All of these therapeutic approaches under active investigation are the result of years of research into the mechanisms that control angiogenesis. They now offer the potential to treat more effectively eye diseases involving neovascularization so that vision loss and blindness can be prevented.

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Science Advances and Future Research Directions

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 2.2 million Americans have glaucoma1, with about half of these unaware that they have the disease. As many as 120,000 are blind from this disease.2 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.

Ocular Hypertension Treatment Study. NEI-supported researchers have discovered that eye drops used to treat elevated pressure inside the eye can be effective in delaying the onset of glaucoma. Scientists found that pressure-lowering eye drops reduced the development of primary open-angle glaucoma (POAG) by more than 50 percent. POAG is the most common form of glaucoma and one of the nation's leading causes of vision loss. The study identified several significant risk factors that were associated with the development of glaucoma in study participants. These included personal risk factors, such as older age and African descent, as well as ocular risk factors, such as higher eye pressure, certain characteristics in the anatomy of the optic nerve, and thinness of the cornea. These results mean that treating people at higher risk for developing glaucoma may delay or possibly prevent the disease.

Early Manifest Glaucoma Trial. The Early Manifest Glaucoma Trial was designed to compare the effect of immediate therapy to lower the intraocular pressure (IOP) versus late or no treatment on the progression of newly detected open-angle glaucoma. The study followed 255 patients, aged 50-80 years, with early stage glaucoma in at least one eye. One group (129 patients) was treated immediately with medicines and laser to lower eye pressure, and a control group (126 patients) was untreated. Both groups were followed carefully and monitored every three months for early signs of advancing disease, using indicators that are extremely sensitive for detecting glaucoma progression. Any patient in the control group whose glaucoma progressed was immediately offered treatment. After six years of followup, scientists found that progression was less frequent in the treated group (45 percent) than in the control group (62 percent), and occurred significantly later in treated patients. Treatment effects were also evident in patients with different characteristics, such as age, initial eye pressure levels, and degree of glaucoma damage. In the treated group, eye pressure was lowered by an average of 25 percent. This finding supports the medical community's emerging consensus that treatment to lower pressure inside the eye can slow glaucoma damage and subsequent vision loss.

Gene Associated with Glaucoma. Even though glaucoma was first described over 100 years ago, there is no complete understanding of its pathogenesis. The hallmark of glaucoma is a distinct pattern of optic nerve degeneration. This degeneration is most commonly associated with elevated intraocular pressure; however, in some patients an elevation in pressure is not evident on clinical examination. Scientists have recently identified a human gene, OPTN, that is linked to a disease known as "low-tension" glaucoma. In patients with this form of the disease, clinicians are unable to detect pathological elevations of intraocular pressure. Four separate mutations in this gene were identified in families in which "low-tension" glaucoma was known to be inherited. Further screening of glaucoma patients suggested that mutations in OPTN may be a risk factor for "low-tension" glaucoma patients. This gene encodes the protein optineurin, which is expressed in a number of tissues including the brain and retina. Optineurin has been shown to interact with other brain proteins such as huntingtin, the protein responsible for Huntington's disease and therefore may have a significant neurological function. Other studies suggest that optineurin participates in a signal transduction pathway involving tumor necrosis factor-alpha, a factor that is believed to increase the severity of optic nerve damage in glaucoma. Increasingly, scientists have viewed protecting the optic nerve as the key to treating the disease. The identification of OPTN as a glaucoma gene provides a tool to study the biochemical pathways leading to optic nerve degeneration, as well as giving insight into designing neuroprotective strategies.

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).

Mutation in Retinitis Pigmentosa Gene Linked to Atrophic Macular Degeneration. Scientists have identified a mutation in a gene on the X chromosome that normally is associated with a form of retinitis pigmentosa (RP) that causes a progressive loss of rod photoreceptors in the peripheral retina and results in blindness in adulthood. This mutation has also been recently reported to cause a unique type of degeneration in the macula, the area of the retina rich in cone photoreceptors that provides our sharp central vision, in a family in which 10 out of 11 affected males had evidence of macular dystrophy. Even though the affected males in this family did not show signs of peripheral retinal degeneration that are normally caused by this locus, the study demonstrates a link between macular degeneration and the locus on the X-chromosome that causes RP and other retinal diseases. Further research may help understand how this mutation specifically targets the macula and causes this unique loss of cones. This may lead to an understanding of the mechanisms of damage in other forms of macular degeneration and perhaps to the development of the means to prevent this type of damage to the macula.

Shedding Light on Biological Clocks. The circadian (daily) clock synchronizes the biological activities of the organism to environmental changes such as light and darkness, temperature, and seasons. Within this 24 hour cycle or rhythm there are variations in mental alertness, sleep-wake patterns, eating habits, and hormonal levels. Although scientists have know for some time that this circadian clock is controlled or reset by light, the cellular events that utilize light to synchronize the circadian clock have remained a mystery until recently. Vision requires light stimulation of specialized sensory neurons called photoreceptors in the retina. Other nerve cells in the retina known as retinal ganglion cells (RGCs) further encode this visual information, transmitting it to either higher visual centers of the brain, such as the optic nerve, or to a non-visual area, the suprachiasmatic nucleus (SCN). The SCN is the circadian rhythm pacemaker of the brain, driving daily biological activities. Damage to the SCN can lead to complete disruption of circadian-linked behaviors, however the SCN can function even in the absence of retinal photoreceptors. Two recent research findings have helped understand how this can be so. Scientists have described a protein, melanopsin, that is present in a subset of RGCs in the retina. Melanopsin belongs to a family of proteins, called photopigments or opsins that are found in retinal photoreceptors and are essential for vision. Those RGCs that contain melanopsin project to the SCN. Other researchers have shown that the RGCs projecting to the SCN respond directly to light stimulation. These findings indicate that those RGCs directly control the circadian pacemaker to drive cyclical biological activities. Future research in this area should provide a new framework to understand and ultimately control complex behaviors such as eating and awake activity.

Identifying Disease Genes in the Visual System. An important barrier to therapeutic intervention in human retinal disease is the identification of the gene or genes that cause vision loss. Visual loss and the degenerative and other changes in the retina are largely linked to rod and cone photoreceptors. Scientists have recently undertaken a comprehensive genetic analysis of rod photoreceptors, the most abundant sensory neuron in the retina, in order to identify all the possible genes expressed in these cells. Rod cells play an essential role in the visual pathway and may be especially vulnerable to any genetic defect involving the retina or other visual centers. For many identified retinal disease genes, either a photoreceptor gene is mutated or its product is altered due to the mutation. A complete database of rod-specific genes would simplify the identification of candidate retinal disease genes. Using the technique of serial analysis of gene expression, or SAGE, in both mature and developing retinal tissues, many new genes in rod photoreceptors have been identified. This work represents an important new strategy for the study of retinal disease.

Light Adaptation Involves the Movement of Proteins. Remarkably, the retina has the ability to adapt to changes in light intensity that allows us to see over a very wide range of illumination. The process by which the visual system changes its sensitivity, depending on the ambient light level is called adaptation. The photoreceptor cells in the retina actually change their sensitivity. This is a slow process that may take many minutes until the visual system is fully adjusted to new light levels. NEI-supported scientists have reported a new cellular mechanism of rod photoreceptor adaptation that is triggered by daylight levels of illumination. The mechanism involves a massive light-dependent translocation of the photoreceptor-specific protein, transducin, between the functional compartments of the rod. Up to ninety percent of the transducin molecules were moved from the rod outer segment, where light is transduced, to other cellular compartments. This transfer occurred on a time scale equal to tens of minutes. The reduction in the transducin content of the rod photoreceptor outer segment was correspondingly accompanied by a reduction in the amplification of the rod photoresponse. The finding that transducin physically translocates in response to light is most significant, not only for the process of light adaptation, but possibly more widely for the process of phototransduction. Previously light adaptation and light transduction were thought to involve only processes of saturation of the involved proteins by light. This new finding shows that this is not the case for adaptation, and suggests protein translocation should be looked for in other steps in the process of signal transduction by photoreceptors.

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 vision ; many others are far-sighted or have astigmatism.

Bacteria Residing in Parasitic Worms Cause River Blindness. Ocular onchocerciasis, commonly known as river blindness, occurs when a nematode worm infects the cornea. Although river blindness is rare in developed countries, it is the second leading infectious cause of blindness in the world. The disease begins with repeated bites from black flies that transmit the nematode larvae. The larvae settle in the skin, where they grow to adulthood, reproduce, and then release millions of microfilariae that travel through the skin and can infect various eye tissues, including the cornea. When the microfilariae die, a massive inflammatory response is observed in the eye. This invasion of immune cells leads to corneal swelling, loss of transparency, and eventually blindness. Development and growth of a microfilaria depends on a bacterium, Wolbachia, which lives within the parasitic worm. Treatment of river blindness with anti-parasitic drugs previously was considered effective, because it reduced the number of microfilariae. However, destruction of the worms leads to the blinding inflammatory response--not due to the worms, but to the bacteria residing within the microfilariae. Upon the death of the parasite, these bacteria are released into the corneal stroma and directly cause the inflammatory reaction that results in blindness. Using a mouse model of river blindness, scientists examined the inflammatory response in corneas subjected to extracts of worms that either were treated with doxycycline antibiotic, to kill the bacteria, or were untreated, and therefore contained living bacteria. When corneas were subjected to bacteria-free worm extracts (i.e. treated with antibiotic), the researchers observed no significant corneal haze or swelling, indicating little or no inflammatory response. This finding indicates the Wolbachia bacterium may be a good target for treatment, not only because it causes the death of the nematode, but also because it can reduce or eliminate the host inflammatory response caused by the bacterium. Further development of this treatment could revolutionize treatment of river blindness, because the prompt destruction and removal of the Wolbachia bacteria should prevent the ensuing blindness associated with ocular onchocerciasis.

Immune Cells in Sjögren's Syndrome. The hallmark of Sjögren's syndrome is severe dry eye and dry mouth. In the eye, the function of the lacrimal gland, which produces the majority of the fluid in the tear film, is severely compromised by infiltration of lymphocytes. The source of the antigens in this autoimmune disease has been attributed to intracellular proteins that are normally not exposed on the cell surface. Availability of these proteins to invading cells may be attributable to cell death. Another mechanism for exposing hidden antigens involves proteins that normally move through lacrimal gland cells in vesicles that shuttle between membranous compartments. This trafficking of proteins may be disrupted, thereby causing misdirection of normally intracellular protein to the surface of cells where they are available to attack by infiltrating lymphocytes. Thus, antigenic proteins normally not available to invading cells in autoimmune disease may arise from multiple sources.

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.

Protein Integrity is Key to Lens Transparency. Age-related cataract formation is believed to result from the complex effects of aging on normal physiological processes. Because the end-result, cataract formation, is in most cases far removed in time from the initial insult, exacting a cause and effect relationship has been difficult. It has long been recognized that lens transparency results from the very high concentration of soluble proteins, the crystallins, within a specialized lens fiber cell. It has also long been known that there is little turnover of proteins within these cells. An adult lens contains proteins synthesized at the earliest stages of embryological development, making fiber cell proteins especially susceptible to the effects of aging. During aging and cataract formation, soluble lens crystallins tend to combine or aggregate into large complexes that cause light to scatter. The normal lens counteracts this aggregation process through the function of "alpha-crystallin, which acts as a molecular chaperone, preventing the unfolding and aggregation of proteins. New research provides data linking the formation of high molecular weight crystallin complexes with diminished chaperone activity. Scientists examined lenses during aging and cataract formation. They found that as "alpha-crystallin acts to prevent the deleterious effect of aggregate formation by binding to other proteins, "alpha-crystallin itself becomes incorporated into an aggregate. Since "alpha-crystallin strongly binds to the lens fiber cell membrane, it becomes a vehicle for complexes to accumulate at the membrane, allowing further damaging physiological effects that may accelerate cataract formation. These new data also showed that the "alpha-crystallin in this membrane-bound aggregate has a significantly diminished capacity to function as a chaperone, indicating that its protective effect has been neutralized. These new studies suggest a possible mechanism of cataract formation. This finding suggests additional research in this area may provide the means for clinicians to intervene prior to the formation of a clinically evident cataract.

Early Eye Development. Development of the lens is one of the earliest events in the development of the eye. Scientists have been attempting to determine the genes that control lens development. Studies have shown that Pax-6 is a master gene that controls the expression of a number of other critical genes. Two critical genes that have recently been identified are Six3 and Grg5. Without the expression of these two genes, the development of the lens is stopped and crystallin?synthesizing cells fail to form. These findings add to our understanding of the overall control of lens and eye development. Identifying developmental genes and their products is essential to the understanding of the hierarchy controlling ocular development and will enhance our knowledge of the molecular basis of congenital diseases of the eye, thereby opening the possibility of future interventions.

Lens Cell Communication and Development. The lens is a dense, compact structure containing two cell types: metabolically active epithelial cells and quiescent fiber cells. Throughout the life-time of an individual, the lens carries out a process of continued growth with epithelial cells dividing and differentiating into fiber cells. Unlike most other tissues, the lens is not nourished by its own blood supply and requires an extensive communication system made up of channels called gap junctions that take up nutrients. Mice with deletions in the proteins that make up gap junctions develop cataracts, as well as developmental abnormalities. Detailed studies in mice in which a deleted gap junction protein is replaced by a related but different gap junction protein have given new insight into the relationship between cell division, differentiation, and communication. These studies highlight the significance of the intricate communication system of the lens and its requirements for maintaining lens transparency. They also provide additional information that may aid in preventing the loss of transparency.

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.4,5 The correction of strabismus is one of the most frequently-performed surgical procedures. 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 (low vision).6 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.

Amblyopia Treatment Study. NEI-supported researchers found that eye drops used to treat a childhood eye disorder work as well as patching the eye. Atropine eye drops were given once a day to treat amblyopia, or lazy eye, the most common cause of visual impairment in children. It was found that the drops work as well as the standard treatment of patching one eye. This research finding may lead to better compliance with treatment and improved quality of life in children with this eye disorder. Patients will continue to be followed in this study to better assess the long term effects these treatments have on visual acuity.

Internal Monitoring of Eye Movements. It is essential to keep track of our own eye movements both for planning sequential movements and for maintaining stable vision despite the sudden retinal shifts caused by the eye movements. A mechanism within the brain that has been hypothesized to perform this vital function is a corollary discharge, that is, a copy or corollary of the neuronal commands that the brain sends out to the muscles to produce movement. Using awake, behaving monkeys as an animal model of the human visual and eye movement system, scientists have studied neurons in a pathway from the brainstem to the cerebral cortex that could convey this corollary discharge. They found that these neurons showed the characteristics expected of a corollary discharge: first the neurons carry information that an eye movement is about to occur, second inactivating these neurons impairs the sequential eye movements dependent upon a corollary discharge and third such inactivation did not affect single eye movements that do not depend on a corollary discharge. These results identify for the first time in the primate visual system neurons that convey a corollary discharge signal. Additional work is under way to determine whether the corollary discharge signals described also are used to produce stable visual perception.

Regeneration: A Developmental Switch. Following injury or disease, neurons in the central nervous system (CNS) have a limited regenerative capacity, unlike nerve cells in the peripheral nervous system. Nerve cells typically have two types of extensions that arise from their cell bodies. Axons are normally quite long and extend over considerable distances. Dendrites are much shorter and extend very short distances from the cell body. The inability of CNS neurons to regenerate is largely due to the failure of their axons to re-grow. It is believed that the inability of CNS axons to regenerate is due to the presence of a non-permissive microenvironment, containing factors that inhibit regeneration. Although these may be important factors, nerve cell interactions may play an inhibitory role as well. Recent work has shown that the developmental state of nerve cells may also play a role in the ability of CNS neurons to regenerate. It is known that postnatal retinal ganglion cells (RGC) in culture do not grow axons as rapidly as RGCs cultured from embryos. Researchers may now have identified a developmental switch that limits the ability of older RGCs to grow axons. They compared growth responses of cultured RGCs from embryonic rats and newborn rats using a wide range of conditions, trophic and other factors, and different substrates. None of these conditions enhanced the ability of RGCs from newborn rats to accelerate the growth of their axons. These results suggest that the ability of neurons to grow axons may in part be due to an intrinsic factor and not dependent on factors in the microenvironment. These scientists also evaluated whether the change in growth rate could be signaled by other retinal cells. Additional co-culture experiments revealed that contact with developing amacrine cells signal RGCs to switch to a dendritic growth mode. The contact between RGCs and amacrine cells not only stimulated the growth of dendrites, but also impaired the growth of axons. If this signal remains in effect long after development is finished it could suppress axonal regeneration in the adult. The present work suggests that a clearer understanding of the developmental switch from axonal to dendritic growth may be a key factor in CNS regeneration. Also, the role amacrine cells play in regulating RGC growth underscores the importance that interneurons may play in suppression of CNS regeneration. The challenge for future work remains to discover the signals that switch neurons back to the axonal growth mode.

Low Vision and Its Rehabilitation
Development of Wayfinding Systems. A major goal of blindness rehabilitation programs is the development of wayfinding systems. This requires a better understanding of the cognitive requirements that underlie the effective use of navigation systems by the visually impaired. Recent work has shown that designers of wayfinding systems can use the mind's ability to use spatial language to update its internal mental image or map of a location or object relative to the body's location. Spatial language describes the location of an object relative to the location of a person's position (e.g. "a chair at 3 o'clock"). Vision researchers studied the role of spatial updating by experimental subjects as they moved using spatial language cues. Spatial updating refers to a person's ability, while moving, to update the location of a target previously perceived while stationary. The researchers were interested in knowing if a subject could navigate to a target using spatial language and updating as effectively as they could using auditory cues. Both blindfolded normally-sighted subjects and blind subjects were used for these studies. All participants were tested on their ability to walk toward a target location after being cued either by auditory stimulus from a loudspeaker or by receiving spatial directions from an investigator. Two results emerged from these studies. The first result suggests that once a subject formed a spatial image it stayed fixed in the environment. The second suggests that once a mental image of a location is formed one can update the representation using either mode of input. Blind subjects were equally adept at spatial updating using spatial language, leading the researchers to conclude that visual experience may not be required for the brain to develop spatial updating skills. The findings also suggest that spatial language can convey information about important off-route landmarks (e.g. phone at 3 o'clock). The results of this study will impact significantly on the development of navigation systems for the blind and visually impaired. Wayfinding systems that use spatial language may be the best approach for development of relatively simple wayfinding systems. This is important because many of the growing number of visually impaired are elderly and require system designs that are easy to use.

Health Disparities
Prevalence of Glaucoma in Mexican Americans. Glaucoma prevalence rates have been reported for white and African American adults, but no similar studies have been conducted among the U.S. Hispanic population. Scientists recently reported the prevalence of glaucoma in a population?based study conducted among 4774 Mexican American adults residing in two communities in Arizona. The prevalence of open?angle glaucoma in this Mexican American population was intermediate between the high rates reported for African Americans and the lower rates reported for whites. Of those diagnosed with glaucoma, only 38% were aware they had the disease. The prevalence of glaucoma increased rapidly with age and was the leading cause of bilateral blindness in this population. This information will allow health educators to create additional glaucoma awareness campaigns to increase awareness of the importance of glaucoma treatment in the Mexican American population, thereby allowing eye care providers to identify and treat those at greatest risk so that blindness can be prevented.

Healthy People 2010
Estimates of Visual Impairment and Healthy Vision Toolkit. The NEI convened a consensus meeting at which many of the world's leading ophthalmic epidemiologists created standard case definitions for the major eye conditions affecting older Americans. With these definitions in hand, data was obtained from a systematic review of all major epidemiological studies. The data from these studies was analyzed to provide prevalence rates for major eye conditions by age, race and gender. These models were then applied to U.S. Census 2000 population data to estimate the number of individuals in each state and the District of Columbia with these eye conditions, providing the most accurate estimates ever produced.. The data and analytical framework used in this project are being published in leading scientific journals and a summary report, Vision Problems in the U.S., was disseminated in 2002 in partnership with Prevent Blindness America. These data will be essential for developing valid and reliable estimates of the economic consequences of these conditions. The NEI continued its support for additional baseline data collection through the National Health Interview Survey and the National Health and Nutrition Examination Survey. NEI staff are continuing their efforts develop a Healthy Vision 2010 Toolkit. Among the components of the toolkit will be a "Community Action Guide" that will discuss opportunities for communities to get involved in Healthy People 2010 and a "Handbook" containing important information on the 10 vision-related objectives.

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New Initiatives

Diabetic Retinopathy Clinical Research Network. The NEI will expand its initiative to support core centers to plan, implement, and conduct clinical trials of the treatment of diabetic retinopathy, diabetic macular edema, and associated conditions. Diabetic retinopathy is a potentially blinding complication of diabetes characterized by the uncontrolled growth of fragile new blood vessels in the retina that may leak fluid and blood threatening vision. It is the leading cause of new cases of blindness in working age adults in the U.S. Macular edema secondary to diabetic retinopathy is also a major cause of visual loss in patients with diabetes. Establishment of the clinical research network of core centers and participating clinics will help satisfy the need to evaluate promising new approaches to treat diabetes induced retinal disorders and to investigate other approaches as they become available. The network will carry out multicenter trials, as opposed to single-center trials, thus reducing the number of patients needed at each clinical center and allowing accrual to be completed more rapidly. Further, a common treatment protocol will reduce variables that contribute to patient outcome and allow valid comparisons between treatments. Finally, the network approach would provide a framework for 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 endpoint evaluation.

Ocular Albinism and the Neuroscience of Retinal Ganglion Cell Axon Guidance. Albinism includes a group of genetic disorders that share a reduction in retinal melanin pigmentation and significant visual abnormalities. The most common form, known as OA1, causes patients to suffer from a variety of other eye conditions, including eye movement disorders, refractive errors, and decreased visual acuity that can compromise vocational choice and quality of life. Oculocutaneous albinism (OCA) is a heterogeneous group of congenital disorders that occurs less frequently. OCA is characterized by a generalized disruption in pigment synthesis in the hair, skin, iris, and inside the eye. OCA and OA1 have similar visual outcomes. The ocular manifestations of both OA1 and OCA include misrouting of retinal ganglion cell axons from the retina to the brain. Axons normally develop and grow along pathways by extending along adjacent axons, and/or by detecting developmental cues. A fundamental question in the development of the visual system is how individual axons respond to these specific cues. Therefore, the abnormal axon routing seen in albinism presents an intriguing model system for developmental studies, particularly since the retinal disorganization is often associated with eye movement disorders and the development of myopia. Expansion of this initiative will allow interdisciplinary collaborations between neuroscientists and cell biologists or basic scientists and clinicians investigating the role of melanin pigment and genetic and other factors in the control of axon guidance in the visual system.

Neurodegeneration and Neuroprotection. Research on neurodegeneration, neuroprotection, and the rescue and regeneration of neural cells is an area of tremendous opportunity for the National Eye Institute with application to many neurological diseases and conditions, and to vision loss from traumatic injury. Neurodegenerative diseases of the eye are among the most devastating of all ocular diseases. In our older citizens, these degenerative diseases cause loss of central and peripheral vision and rob them of their independence by impairing their ability to perform or enjoy even the most routine activities. These diseases cause our young and working age citizens to be continually challenged in the daily activities that the rest of us take for granted. Because this is a priority area of research at the NEI, an initiative in neurodegeneration and neuroprotection is needed to continue to address basic research opportunities, and where appropriate, should also begin translational studies for moving advances into the medical arena as well. A number of approaches show promise, including the use of neuroprotective agents, growth factors, use of stem cells, transplantation, ribozymes, and other methods of gene transfer and gene?based therapy.

Control of Angiogenesis. Diabetic retinopathy, retinopathy of prematurity, neovascular glaucoma, and age-related macular degeneration are characterized by a proliferation of abnormal blood vessels that can result in the rapid and irreversible loss of vision and are among the leading causes of blindness in this country. Eye diseases characterized by angiogenesis (the growth of new vessels) or neovascularization (the proliferation of abnormal vessels) have profound effects on eye and vision health and cause economic loss for our society and the patients afflicted. The ability to prevent selectively or increase the formation of new blood vessels or to cause their regression selectively would have a tremendous impact on the treatment of a number of serious diseases, including cancer, heart disease, age?related macular degeneration, and the vascular complications of diabetes. Vascular endothelial growth factor (VEGF) antagonists and PKC inhibitors are among the agents that are being investigated as possible new treatments for these eye conditions. This area of research remains a high priority area.

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Innovations in Management and Administration

Intramural Research Program. As part of the effort to revitalize the NEI intramural program, a nationwide search was conducted to fill the institute's vacancy for the Scientific Director position. University of California, Berkley Professor Sheldon S. Miller, Ph.D. was named to fill the position as head of the NEI Division of Intramural Research. The appointment of someone with Dr. Miller's scientific and administrative credentials will bolster the NEI's Intramural Research Program and enhance its national prominence.

NEI Strategic Planning. The NEI has begun development of the next plan in its nearly 30 year history of strategic planning. The current effort will be divided into two phases. Phase one of the process will involve reviewing and updating the goals and objectives from the previous plan in conjunction with the vision research scientific community, members of the National Advisory Eye Council, and professional and lay groups that support vision research. Phase two of the process will involve a series of meetings or workshops on cutting edge topics facing the research community. These meetings will help identify the greatest needs and opportunities for research in the field. The first of these meetings was held in November 2002 and was entitled "The Pathophysiology of Retinal Ganglion Cell and Optic Nerve Degeneration." This meeting provided a forum for open scientific discussion between experts in glaucoma research and experts in other fields of neuroscience that deal with damage and degeneration of central nervous system neurons. It is hoped that the recommendations from this meeting, and others like it, will yield new insights and strategies for dealing with the research challenges in diseases of the eye and disorders of vision.

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Budget Policy

The Fiscal Year 2004 budget request for the NEI is $648,299,000 including AIDS, an increase of $23,223,000 and 3.7 percent over the FY 2003 amended President's Budget Request. A five year history of FTEs and Funding Levels for NEI are shown in the graphs below. Note that Fiscal Years 2001 and 2000 FTEs are not comparable for the NIH Human Resources functional consolidation.

Full-Time Employees by Fiscal Year 2000-2004

Funding Levels by Fiscal Year 2000-2004

NIH's highest priority 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. NEI will provide an aggregate average cost increase of 4.0 percent for Research Project Grants (RPGs).

Also in FY 2004, NEI will fully fund 5 grants; 2 of them will be Academic Research Enhancement Awards, and 3 of them will be Small Grants for Pilot Research.

Promises for advancement in medical research are dependent on maintaining the supply of new investigators with new ideas. In the Fiscal Year 2004 request, NEI will support 289 pre- and postdoctoral trainees in full-time training positions, the same number as in FY 2003. Stipend levels for NRSA trainees will increase by 4 percent over Fiscal Year 2003 levels for predoctoral fellows, and from 4-1 percent, based on years of experience, for postdoctoral fellows.

The Fiscal Year 2004 request includes funding for 40 research centers, 170 other research grants, including 55 clinical career awards, and 76 R&D contracts. Also, within the FY 2004 R&D funding is $1,410,000 targeted to the Best Pharmaceuticals for Children's Act. Intramural Research and Research Management and Support receive increases of 4.1 and 4.0 percent, respectively, over FY 2003. These increases will help fund a continuing reinvigoration of the NEI Intramural Research and Extramural Research programs, to maximize the operational efficiency and effectiveness of these programs.

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

FY2004 Budget Mechanism

FY2004 Estimate Percent Change from FY2003 Mechanism

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Department of Health and Human Services NIH, the National Institutes of Health USA.gov