For more than 20 years, the National Eye Institute (NEI) and the National Advisory Eye Council (NAEC), through its Vision Research Program Planning Subcommittee, have attempted to conscientiously meet their stewardship responsibilities through a comprehensive planning process. This process has resulted in the development and publication of a series of strategic plans that address the most pressing visual health needs of the Nation. These plans have been developed in partnership with the full Council, NEI staff, and numerous members of the vision research community, and with supporters in countless scientific, voluntary, and philanthropic organizations throughout the country. This plan is sixth in the series that dates back to the publication of Vision Research Program Planning in 1975.
VISION STATEMENT AND MISSION
Our eyes and the parts of our brain that allow us to understand the visual information we receive from our eyes comprise a unique and awe-inspiring sense known as sight. Our eyesight provides intimate detail of our daily life in the world around us. It allows us to recognize the faces of those who are important to us and to perform complex tasks for work or pleasure that would otherwise be impossible.
Out of its concern for the eyesight of the American people, Congress created the NEI in 1968. In recognition of its special responsibility to address the visual health needs of the Nation, the NEI and the NAEC offer this vision and commitment for the future:
The National Eye Institute will continue to protect and improve the visual health of the Nation through the support and performance of the highest quality laboratory and clinical research aimed at increasing our understanding of the eye and visual system in health and disease and developing the most appropriate and effective means of prevention, treatment, and rehabilitation, and through the timely dissemination of research findings and information that will promote visual health.
This vision statement is the logical extension of the NEI 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 the blind.”
Inherent in this mission is the investigation of normal tissue and normal visual processes, so that a more complete understanding may be gained of the abnormal processes that lead to diseases of the eye and disorders of vision. 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.
DEVELOPMENT OF THE 19992003 PLAN
In the development of this plan, panels of over 100 experts were assembled to represent each of the NEI’s five formal programsRetinal Diseases; Corneal Diseases; Lens and Cataract; Glaucoma; and Strabismus, Amblyopia, and Visual Processingalong with specialized groups representing Visual Impairment and Its Rehabilitation and Health Services Research. Information was also solicited for the panels through the NEI homepage (http://www.nei.nih.gov/). Visitors to the homepage were provided the opportunity to comment on the most significant accomplishments or advances since the last plan and recommend the most important vision research questions that should be addressed during the next 5 years. This information was then passed along to the panels for consideration in preparing their reports.
Each panel was asked to prepare a report that had the following elements: a program overview and goals; assessment of the progress within the program, particularly related to the goals and objectives in the last plan; program objectives that are the primary focus for research in the program; the research needs and opportunities that give rise to each objective; and strategic research questions that will lead to achievement of the goals and objectives.
It is important to note, however, that the NEI and the NAEC do not view this plan, nor its predecessors, as blueprints or master plans for research, but rather as vehicles to draw attention to areas of research need and opportunity. Our first priority has been and continues to be funding the highest quality investigatorinitiated research applications that will help achieve the goals and objectives outlined in these plans. To that end, the principal factor considered in determining which applications are funded continues to be the scientific merit of the proposal, as evaluated through the peer review system, combined with the programmatic considerations of the NAEC. It is with this in mind that the following summary of the programs, goals, highlights of research progress, and research objectives are presented for Fiscal Years 1999 to 2003.
RETINAL DISEASES PROGRAM
The retina is a complex tissue in the back of the eye that contains specialized photoreceptor cells called rods and cones. They are connected to a network of nerve cells for the local processing of visual information. This information is sent to the brain for decoding into a visual image. The adjacent retinal pigment epithelium (RPE) supports many of the retina’s metabolic functions.
The retina is susceptible to a variety of diseases that can lead to visual loss or complete blindness. One such disease, diabetic retinopathy, is a major cause of blindness. In the proliferative stage of the disease, newly formed abnormal blood vessels can break through the retinal surface and hemorrhage into the normally transparent, gelatinlike vitreous in the middle of the eye. Scar tissue may subsequently form and pull the retina away from the back of the eye, causing a retinal detachment to occur. Laser treatment (laser photocoagulation) is a highly effective clinical tool for treating proliferative retinopathy.
The two most common forms of cancer that affect the eye are retinoblastoma (RB) and choroidal melanoma. RB is mainly a disease of childhood. Through the advances achieved over the past few years, RB is now one of the best understood of all solid tumors. It has also opened new opportunities in the etiology of other cancers. Choroidal melanoma primarily affects adults, and its etiology is poorly understood.
The inherited retinal degenerations are typified by retinitis pigmentosa (RP), which results in the destruction of photoreceptor cells, and the RPE. This group of debilitating conditions affects approximately 100,000 people in the United States. The leading cause of visual loss in the elderly is macular degeneration (MD), which has an increasingly important social and economic impact in the United States. As the size of the elderly population increases in this country, agerelated macular degeneration (AMD) will become a more prevalent cause of blindness than both diabetic retinopathy and glaucoma combined. Although laser treatment has been shown to reduce the risk of extensive macular scarring from the “wet” or neovascular form of the disease, there are currently no effective treatments for the vast majority of patients with MD.
One of the major achievements in all of biology has been in defining cellular events involved in the process of visual transductionthe process that describes the capture of light by the photoreceptor cells and the initiation of the electrical signals utilized by the brain in processing visual information. This is now a classic model of how signal processing works in other systems. Advances in understanding visual biochemistry have yielded important new insights into the causes of retinal diseases.
The brain decodes and interprets the visual images that we perceive when electrical impulses generated within the retina are transmitted by ganglion cells via the optic nerve to the visual cortex of the brain. The tools of modern neurobiology offer the potential to understand both light adaptation (sensitivity to varying light levels) and inactivation (turning off of the sensitivity to light). A central unanswered question in neurobiology is how the complex retinal network permits the formation of images and the discrimination of colors.
After a thorough evaluation of the entire program, the Retinal Diseases Panel recommends the following goals for the program for the next 5-year period.
- Understand the molecular and biochemical basis for the different forms of MD, improve early diagnosis, characterize environmental effects on the etiology of MD, and develop new treatments.
- Understand the pathogenesis of diabetic retinopathy and other vascular diseases of the retina and develop strategies for primary prevention and improved treatment.
- Identify the genes involved in retinal degenerative diseases, including RP, and determine the pathophysiological mechanisms underlying these mutations.
- Explore new potential therapeutic strategies for inherited retinal diseases, such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention.
- Establish the causes and etiology of uveitis and improve methods for its diagnosis, therapy, and prevention.
- Use both molecular and physiological approaches to study light adaptation in photoreceptors, with particular emphasis on the visual cycle.
- Build on knowledge gained from retinal neuroscience to understand how retinal networks process visual images, a central unanswered question of modern neurobiology.
Highlights of Recent Progress
Genes for a number of different forms of heritable macular disease have been mapped to specific chromosomes and, in some cases, the mutated genes have actually been identified. Detection of genes mutated in AMD will permit the development of genetic tests that may identify individuals at risk for the disease.
Aldose reductase, the initial enzyme of the “sorbitol pathway,” may be critical for the development of diabetic retinopathy. A potent new aldose reductase inhibitor has been developed that inhibits the enzyme by approximately 90 percent and prevents vascular endothelial growth factor (VEGF), a factor that has been linked to the abnormal growth of retinal blood vessels or neovascularization, expression in long-term galactosemic rats.
VEGF has become a leading candidate as the agent responsible for neovascularization in retinal and choroidal diseases. This growth factor is present at high concentrations in the vitreous of patients with proliferative diabetic retinopathy and is low to absent in the vitreous of patients with nonvasoproliferative disease.
At least 10 genes causing RP have been identified. At least 24 additional loci causing RP have been placed on the human genome map and are in varying stages of being identified through positional cloning strategies.
Transgenic animals expressing genetic mutations in patients with inherited retinal degenerations have been developed. These animal models are already the subject of intensive study to determine the pathophysiological mechanisms whereby these gene defects lead to photoreceptor degeneration.
Progress has been reported in developing effective strategies for retinal disease, particularly in the area of somatic gene therapy using different delivery systems. Significant slowing of photoreceptor degeneration has been documented in several animal models with the administration of growth factors. Human trials may begin within this year.
A double-masked clinical trial of about 600 patients with RP found that oral vitamin A supplementation slowed the course of retinal degeneration, as measured by the electroretinogram, and that vitamin E hastened it.
Bacterial lipopolysaccharide has recently been exploited as an experimental inducer of uveitis (an intraocular inflammation) in mice and rats, and this newer model has considerably enhanced understanding ocular inflammation due to immunopathogenic, rather than autoimmune, processes.
The molecular components of the visual transduction pathway have been described in considerable detail. A significant advance has been the identification and characterization of the guanylate cyclase activating proteins. These proteins regulate the activity of guanylate cyclase and play a role in photorecovery and light adaptation.
The NEI-sponsored clinical trial entitled Studies of the Ocular Complications of AIDS (SOCA) has demonstrated that for AIDS patients with cytomegalovirus (CMV) retinitis a combination therapy with foscarnet and ganciclovir is more effective than either drug alone in controlling it. A recent advance has been the development of a sustainedrelease ganciclovir device that is surgically implanted into the vitreous cavity and releases drug over several months. There is a significant delay in progression of CMV retinitis for patients receiving the implant.
Progress has been made in signal processing in the retina on two fronts: understanding the codes by which visual information is signaled, and understanding the way the retina transforms incoming information. A new technique for recording signals in the optic nerve has been created that depends on powerful computers. Many optic nerve fibers can now be studied simultaneously, allowing patterns of activity that were once thought insignificant to be analyzed for their information content.
After carefully considering the research advances that have been made in this program, and based on a careful analysis of the current research needs and opportunities, the Retinal Diseases Panel recommends the following laboratory and clinical research objectives:
- Explore the pathophysiological heterogeneity of AMD to hasten development of the tools needed for improved diagnosis, prevention, and therapy.
- Investigate the pathogenesis of vascular diseases of the retina and choroid, including diabetic retinopathy, AMD, and retinopathy of prematurity (ROP); develop better methods of prevention and therapy.
- Identify novel causes of inherited retinal degenerations; further examine the cellular and molecular mechanisms whereby identified gene defects cause retinal degenerations.
- Further develop and critically evaluate therapies involving gene delivery, growth factors, and transplantation for the treatment of retinal disease.
- Explore the cellular and molecular basis of the response to retinal injury.
- Identify the factors that dictate the unique properties of intraocular immunity and inflammation and alter systemic immunity to intraocular antigens.
- Develop diagnostic methods and therapeutic approaches that distinguish among infectious, immunopathogenic, and autoimmune posterior segment intraocularinflammation.
- Analyze the mechanisms underlying light adaptation and recovery following phototransduction.
- Study how visual information is transformed by successive layers of the neural retina and the mechanisms involved.
- Identify and characterize factors important in retinal cell fate determination and differentiation.
- Catalog, map, and functionally characterize genes expressed in the retina and choroid and begin to determine the cellular sites of retinal gene expression in health and disease.
- Probe the control of the retina’s microenvironment through studies of Brüch’s membrane, the interphotoreceptor matrix, the RPE, glia, choroid, and vitreous.
CORNEAL DISEASES PROGRAM
The cornea is the transparent tissue at the front of the eye that serves two specialized functions: it forms a protective physical barrier that shields the eye from the external environment, and it serves as the main refractive element of the visual system, directing incoming light onto the lens. Refraction depends on the cornea acquiring transparency during development and maintaining this throughout adult life. In this country, corneal diseases and injuries are the leading cause of visits to eyecare clinicians, and are some of the most painful ocular disorders. In addition, 60 percent of the American population have refractive errors that could be corrected for sharper vision.
After a thorough evaluation of the entire program, the Corneal Diseases Panel recommends the following goal for the program for the next 5-year period.
- Understand the normal function of the cornea and apply this knowledge to the prevention and treatment of traumatic injury and disease.
Highlights of Recent Progress
Recent NEI-funded research has led to great progress in understanding and treating corneal disorders. Much has been learned about new molecular detail of the processes of hydration control that are crucial to maintaining corneal transparency, through the discovery of watertransporting elements called aquaporin proteins. The genes for these transporters have been cloned and sequenced and their functional properties are being determined.
Genetic studies in families afflicted with corneal dystrophies have yielded new insight into the pathogenesis of 13 different corneal dystrophies. Their causative genes have been identified, and the challenge now is to clone the responsible genes to help understand the etiology and pathogenesis of these conditions. This understanding should also lead to improved methods of diagnosis and treatment. The most common corneal dystrophy in the United States is keratoconus, a progressive thinning of the cornea, which causes it to become cone shaped. This disease has become better understood as a result of investigation of its genetic predisposition, detection of early cases through computerized topographic analysis, and initiation of a clinical prospective assessment of the progression of the disease in the Collaborative Longitudinal Evaluation of Keratoconus Study or CLEK.
Using molecular biology techniques, researchers have now determined many of the molecules involved in transparency and how they function. Researchers know the origin of the cells that continuously replace those of the corneal epithelium, and they know some of the factors involved in their regulation. This knowledge was recently applied to restoring the disease-damaged corneal surface of a patient with cells grown from the patient’s other, nondiseased eye.
There is mounting evidence that the pathology of many corneal infections is mediated by the immune system. This is particularly clear in the case of infection with herpes simplex virus-1. Infection of T-cell-deficient mouse strains fails to produce corneal inflammation, and mice with corneas purged of antigenpresenting cells develop a milder keratitis than animals with normal corneas. Additionally, individuals infected with the human immunodeficiency virus (HIV) usually do not develop stromal keratitis.
Researchers have improved their understanding of the causes of dry eye in recent years. The nature and regulation of tears is better understood, and much work has been done on the function of mucins (components of tear fluid), hormonal regulation of tear production, and the function of the lipid layer. Changes in lacrimal gland innervation and electrophysiology have been found to precede local autoimmune phenomena in mouse models for Sjögren’s Syndrome, an autoimmune disease in which dry eye is a significant symptom. A new autoantigen (cytoskeletal -fodrin) has been implicated in Sjögren’s Syndrome autoimmunity, suggesting improved diagnosis and new therapeutic approaches.
Understanding how the cornea metabolizes lipids (fatty molecules) to form mediators of inflammation and wound healing has advanced in recent years. Recent focus has been on the fatty acid called arachidonic acid. Specific enzymes transform arachidonic acid into prostaglandins, which are substances that can alter blood vessel permeability and platelet aggregation. This transformation is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Several NSAIDs have been introduced into the clinical armamentarium during the past few years. These are beneficial in relieving symptoms of allergic conjunctivitis and in pain and inflammation control following refractive surgery or cataract extraction.
Research on the cornea has generated knowledge that can be applied to problems in other organ systems. For example, studies on the properties of the eye that make the cornea a privileged immune site, i.e., one in which normal immune responses do not occur, raise the possibility that this property can be conferred to other tissues. This may facilitate the transplantation of other organs. Studies on the molecular structure of corneal collagen, a key structural protein, not only provide information on the assembly of this tissue, but also contribute insight into developmental defects of the skeletal system and the skin. Since the cornea is constantly exposed to ultraviolet light and oxidative damage, it has provided information on ways that cells can protect themselves from this damage.
After carefully considering the research advances that have been made in this program, and based on a careful analysis of the current research needs and opportunities, the Corneal Diseases Panel recommends the following laboratory and clinical research objectives:
- Explore the molecular basis of corneal transparency.
- Analyze the molecular nature of corneal inflammation and wound healing.
- Delineate the pathogenesis of corneal developmental anomalies and dystrophies.
- Improve the understanding of ocular surface physiology.
LENS AND CATARACT PROGRAM
In contrast to the cellular and molecular complexities present in most other tissues, the lens is a much simpler system, composed of a single layer of epithelial cells that differentiate into fiber cells. The ease of obtaining lens epithelial and fiber cells, plus the relative molecular simplicity of the fully differentiated fiber cells, make the lens one of the best tissues to study events that control aging.
Nonetheless, it is the transparent properties of the lens and its ability to focus light that present some of the most clinically relevant challenges in eye research. Cataract is an opacity in the normally clear lens that interferes with vision. Cataract is an immense medical problem, whose eventual cure almost certainly depends on increased understanding of the basic molecular processes occurring in the normal and cataractous lens. By far the most serious problem associated with the lens is its loss of transparency, but most people in midlife face another problem associated with the lenspresbyopia. Presbyopia is the loss of the ability of the lens to focus from distant to near (known as accommodation). By understanding the changes in physical properties of the normal lens and its surrounding support structures as a function of age, it may be possible to develop treatments that delay or prevent presbyopia.
The objectives listed in this report have been selected with the assumption that understanding basic lens physiology will provide the framework for learning more about mechanisms involved in presbyopia and cataract and thereby allow researchers to develop more effective treatments.
After a thorough evaluation of the entire program, the Lens and Cataract Panel recommends the following goals for the program for the next 5-year period.
- Understand the physiological basis of lens transparency on the cellular and molecular levels.
- Determine the causes and mechanisms of cataract formation.
- Characterize the controls of lens cell division and differentiation and their roles in the formation of posterior subcapsular and secondary cataracts.
- Understand lens development and the diseases associated with defects in this process.
Highlights of Recent Progress
An important recent discovery has been that -crystallins, a major structural component of lens cells, prevent damage by denaturation and aggregation of proteins. This novel finding suggested a particularly significant role for this important class of proteins as a molecular chaperone. Chaperones are proteins that affect protein-protein interactions by stabilizing proteins and preventing other damage when exposed to heat or other environmental stresses.
Progress has also been made in characterizing structural changes that occur to lens proteins during the normal aging process. Advances in technological capabilities have led to the identification of sites where modifications to lens proteins occur. None have yet been specifically associated with age-related cataract, but rather seem to be part of the normal aging process.
Advances in understanding the lens cell cycle have centered around the discovery that the protein made by the RB gene is the central gatekeeper that prevents the lens fiber cells from entering into the cell cycle and, hence, from proliferating. This protein also plays a key role in preventing apoptosis or programmed cell death in the lens and other organs.
Growth factors are involved in all stages of lens development, and their relevance to maintaining a healthy lens has been firmly established. Over the last 5 years, much has been learned about how growth factors signal lens differentiation, regulate the cell cycle, and impact on lens transparency. Experiments indicate that members of the fibroblast growth factor family are prime candidates for the retina-derived inducers of fiber cell differentiation during lens development and the molecules responsible for maintaining the balance between differentiation and division in the nature lens.
The identification of mutations in the Pax-6 gene as being responsible for causing aniridia, a congenital malformation of the eye, was a major breakthrough not only in understanding this disease, but in understanding the developmental processes controlling eye development. This was the first gene to be shown by genetic function to be essential for normal vertebrate eye development.
The identification and characterization of gap junction proteins have also been important in understanding the function of gap junction in the maintenance of lens transparency. Gap junctions contain channels between cells that provide an aqueous pathway between adjacent cells, allowing them to share ions and small molecules. Because the lens is avascular, it has been hypothesized that gap junctions between lens cells play a crucial role in inter-cellular metabolic support essential for lens survival.
After carefully considering the research advances that have been made in this program, and based on a careful analysis of the current research needs and opportunities, the Lens and Cataract Panel recommends the following laboratory and clinical research objectives:
- Determine if there are novel markers that differentiate the normal aging process from the diseased (cataractous) state.
- Definitively test hypotheses of cataract.
- Map, identify, and characterize genes which, when mutated, cause congenital or age-related cataract; determine if there are genetic factors that interact with environmental factors to confer susceptibility to age-related cataract.
- Identify genes and pathways that control eye development, especially those critical for lens induction, cell fate determination, and cell differentiation.
- Define the contributions of crystallins to normal lens function.
- Characterize the control of the cell cycle in lens epithelial cells by identifying cell cycle regulators, growth factors, receptors, and signal transduction pathways.
- Characterize, at the molecular level, the ion channels, transporters, and gap junction proteins needed to maintain lens homeostasis; determine what roles perturbations in these systems play in cataract formation.
- Define the mechanisms that regulate the cellular and subcellular architecture of the lens, with special emphasis on the contribution of minor constituents and theirprogressive modification during aging and opacification.
- Understand the basis of lens accommodation and presbyopia at the molecular and mechanistic levels.
Glaucoma is not a uniform disease but rather a heterogeneous group of disorders that share a distinct type of optic nerve damage that leads to loss of visual function. The disease is manifest as a progressive optic neuropathy that, if left untreated, leads to blindness. It is estimated that as many as 3 million Americans have glaucoma and, of these, as many as 120,000 are blind as a result. Furthermore, it is the number one cause of blindness in African-Americans. Its most prevalent form, primary open-angle glaucoma, can be insidious. This form usually begins in midlife and progresses slowly but relentlessly. If detected early, disease progression can frequently be arrested or slowed with medical and surgical treatment.
The overall emphasis for research in this program is on identifying the biological mechanisms responsible for glaucoma so that improved treatment can be developed. Continued laboratory and clinical research has provided a greater understanding of the normal functions of the ocular tissues involved in this disease. Such studies have led to the introduction of a variety of new drugs to reduce intraocular pressure; the development of new diagnostic tools; better estimates of disease prevalence; and, most importantly, the identification of glaucoma genes.
After a thorough evaluation of the entire program, the Glaucoma Panel recommends the following goals for the program for the next 5-year period.
- Develop improved measures to aid in the clinical diagnosis of glaucoma; monitor progression of disease and treatment effectiveness; and elucidate the pathophysiology and natural history of the disease.
- Understand the molecular and biochemical basis of aqueous humor dynamics, with special emphasis on outflow.
- Identify genetic loci and genes contributing to glaucoma, especially those responsible for the common forms of the disease.
- Determine the mechanisms of optic nerve damage and retinal ganglion cell loss and survival in glaucoma.
Highlights of Recent Progress
The development of new diagnostic and imaging methods provides more reliable and objective methods for early diagnosis of glaucoma and for determining progression of glaucomatous damage. Unlike traditional methods that are based on detection of a small increment of white light on a white background, the new procedures are designed to isolate and measure those visual functions mediated by specific cell populations damaged in glaucoma.
Epidemiological studies conducted in the United States and the West Indies have improved the prevalence and incidence estimates of primary open-angle glaucoma among white and black populations. One strength of these recent studies is the adoption of more inclusive definitions of primary open-angle glaucoma that require th