FUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2009 Jayakrishna Ambati, M.D. Chi-Chao Chan, M.D. Albert O. Edwards, M.D., Ph.D. Ali Hafezi-Moghadam, M.D., Ph.D. Josephine Hoh, Ph.D. Xuri Li, Ph.D. Andrew Lotery, M.D. Xiaoxi Qiao, M.D., Ph.D. Dennis W. Schultz, Ph.D. Robin L. Seitzman, Ph.D. Allen Taylor, Ph.D. Heping Xu, Ph.D. Caroline J. Zeiss, Ph.D.
FUNDING PERIOD: APRIL 1, 2006 – MARCH 31, 2008 Steve Abcouwer, Ph.D. Qiuyun Chen, Ph.D. Xi-Qin Ding, Ph.D. Elia Duh, M.D. Michael Gorin, M.D., Ph.D. Jeffrey Gross, Ph.D. Marc Kantorow, Ph.D. Nancy Mangini, Ph.D. John O’Brien, Ph.D. David Pepperberg, Ph.D. Enrique Rodriguez-Boulan, M.D.
FUNDING PERIOD: APRIL 1, 2005 – MARCH 31, 2007 Jiankang Liu, Ph.D. Jiyang Cai, Ph.D. James T. Handa, M.D. *H. Criss Hartzell, Ph.D. *Breandán N. Kennedy, Ph.D. Heidi R. Vollmer-Snarr, Ph.D.
FUNDING PERIOD: AUGUST 1, 2004 - JULY 31, 2007 International Award Nicolas G. Bazan, M.D., Ph.D.
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FUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2009
Jayakrishna Ambati, M.D.
University of Kentucky
Lexington, KY
Project: The Role of SPARC in Macular Propensity for CNV
$100,000
Age-related macular degeneration is as common as cancer in the United States. The principal cause of vision loss AMD is choroidal neovascularization (CNV), the growth of abnormal blood vessels (angiogenesis) beneath the retina. CNV is devastating because it occurs almost always in the macula, the central retina that provides fine vision. The reason for this macular propensity is unknown. We have identified a protein called SPARC that is present almost exclusively in the macula and increased in AMD. We have also shown that the presence of SPARC is necessary for VEGF-A, a potent molecule that promotes angiogenesis, to perform this function. We have also shown that the presence or absence of SPARC determines whether VEGF-A acts via VEGF receptor-1, which suppresses angiogenesis, or VEGF receptor-2, which promotes angiogenesis. We will determine the levels of SPARC, VEGF-A and the activity of VEGF receptors in the macula and peripheral retina in patients with or without AMD, and whether blocking SPARC reduces CNV in animal models. We will determine whether the differential distribution of SPARC underlies the macular propensity of CNV and whether modulating SPARC will reduce the attractiveness of the macula for CNV development, thereby permitting improved vision in patients with AMD.
Chi-Chao Chan, M.D.
Institution: National Eye Institute
Bethesda, MD
Project: Chaperone and Age-Related Macular Degeneration Model
$100,000
Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in the USA and developed countries. Currently there is no treatment for the disease. AMD results from damage to the retina, a neuronal tissue in the eye that is responsible for vision. We have established a mouse strain, which shows many AMD features. We hypothesize that these features may result from accumulation of certain toxic proteins in retinal cells. We propose to study this mouse model and identify the specific toxic proteins. We plan to find therapies to eliminate these toxic proteins and treat AMD.
Albert O. Edwards, M.D., Ph.D.
Mayo Clinic
Dallas, TX
Project: Genome-wide scan of nsSNPs
$100,000
The discovery of genetic variation increasing the risk of macular degeneration has revolutionized our understanding of how patients lose vision from this condition. These discoveries have relied upon the study of changes in our DNA sequence in large groups of persons with and without macular degeneration. The genetic risks discovered to date change the sequence of proteins in our bodies. We believe that additional variation in protein sequence will be found to alter the risk of developing macular degeneration or its complications that lead to blindness. We propose to systematically screen all known common variation changing the sequence of proteins to determine if they alter the risk of developing AMD. These experiments are expected to discover new pathways for developing AMD and improve our understanding of how the disease develops.
Ali Hafezi-Moghadam, M.D., Ph.D.
Harvard Medical School
Boston, MA
Project: Role of a Novel VEGF Effector on CNV in a Model of AMD Recommended:
$100,000
Age-related macular degeneration (AMD) is the leading cause of vision loss in people over age 55 in the US. This disease causes a loss of central vision, making people with AMD unable to read, drive, or recognize faces. In the wet form of AMD, abnormal, leaky blood vessels develop under the retina, causing damage to the surrounding tissue. Important new therapeutic strategies target VEGF, a molecule that plays a role in producing the leakiness of the blood vessels in AMD. Since it is not completely understood how VEGF achieves these effects, the objective of this proposal is to investigate the molecular links between VEGF and retinal vascular leakage. We identified a molecule released by immune cells that is a likely culprit in the damage to retinal blood vessels, causing their leakiness. We hypothesize that VEGF is largely producing its destructive effects in AMD directly through this molecule. Our preliminary data support this hypothesis, as we find that blocking this molecule greatly reduces the size of vascular lesions formed in a laser-induced model of AMD. We propose to further investigate these molecular links in tissues from human patients. Our approach may provide a more effective and specific target for treatment, which would mean a substantial benefit to AMD patients.
Josephine Hoh, Ph.D.
Yale University
New Haven, CT
Project: AMD beyond Complement and Serine Protease Pathways
$100,000
Age-related macular degeneration (AMD) has a complex etiology and is broadly classified as either dry or wet. The dry form is more common, accounting for approximately 90% of patients, and does not typically result in blindness. About 10% of patients have the wet form, in which central vision will be destroyed. We have identified two major genetic factors predisposing some individuals to the more aggressive wet form of AMD and others to the slowly progressing dry type. Together with the new risk factors we will discover, it will be possible to detect who is at increased risk and allow those affected to take preventive measures.
Xuri Li, Ph.D.
NIH/NEI
Bethesda, MD
Project: PDGF - C/D in Choroidal Neovascularization and AMD Therapy
$100,000
Reagents that can suppress the growth of undesired blood vessels have shown beneficial effects for some AMD patients. However, none of them can halt or reverse the course of the disease. New anti-angiogenic reagents are therefore still needed. The platelet-derived growth factor C (PDGF-C) and PDGF-D are two promising candidate molecules to be targeted. Our previous and current work has shown that both PDGF-C and PDGF-D are potent angiogenic factors with potential important roles in choroidal neovascularization (CNV). This study is thus designed to test the role of PDGF-C and PDGF-D in the development and growth of undesired new blood vessels in the choroids and retina. Multiple approaches including different CNV mouse models, PDGF-C deficient and transgenic mice, neutralizing antibodies and siRNA, etc, will be used to achieve our scientific goals. Results derived from this study investigating the angiogenic nature of PDGF-C and PDGF-D in CNV formation and progression, as well as the anti-angiogenic effects of PDGF-C/D antagonists alone and in combination with other angiogenesis inhibitors will provide not only new insights into the basic molecular and cellular mechanisms of CNV formation in neovascular AMD, but also possibilities of novel therapy for the treatment of AMD patients.
Andrew Lotery, M.D.
University of Southhampton
Southampton, UK
Project: Study of Complement and HLA Related AMD
$100,000
Age related macular degeneration (AMD) is the commonest cause of blindness in the western world. As current treatments are extremely limited, it is vital to improve understanding of this disease in order to develop better treatments. Happily, progress is being made. Recent work on complement factor H (CFH) and by us on Human Leucocyte Antigens (HLA) have highlighted the importance of inflammation in the development of AMD. Our proposed research will use modern molecular genetic techniques to test whether 1) there are other, related complement genes which also cause AMD, 2) there is a microbial trigger activating the complement cascade in AMD and 3) investigate how HLA associations lead to AMD. If these experiments are successful, our understanding of the biology of complement and “HLA related age related macular degeneration” could be radically altered. This offers the best hope for tailoring current AMD management and developing novel treatments for this prevalent cause of blindness.
Xiaoxi Qiao, M.D., Ph.D.
Indiana University
Indianapolis, IN
Project: TFPI-VLDLR Pathway in Retina Angiogenesis
$100,000
Age-related macular degeneration (AMD) is the most common cause of severe and irreversible vision loss in older adults in the US. The key lesion in the eye is abnormal vasal growth in the retina. Although several risk factors have been named, what molecule triggers the abnormal vasal growth is still not clear. A recent study reported that similar abnormal vasal growth was found in the eyes of a mutant mouse which lacks very low density lipid receptor (vldlr). The current proposal is to examine the role of vldlr as well as its known up and down stream molecules on the abnormal vasal growth in the eye. We will use this mutant mouse model and look for potential differences between the normal control and the mutant mice. We will also use retinal vascular cell culture to determine if vldlr and related molecules are the key pathway to stimulate abnormal vasal growth. Identify key molecules responsible for abnormal vasal growth will provide us new targets to develop better treatment strategy for AMD.
Dennis W. Schultz, Ph.D.
Oregon Health & Science University
Portland, OR
Project: Characterization of 10q26 AMD Protein
Recommended: $100,000
Age-related macular degeneration (AMD) is the most common disease leading to blindness in the United States. It is responsible for about half of all registered cases of blindness. Because our elderly population is growing, this will only become a bigger problem in the future. Furthermore, there are not as yet, any really good treatments available and early diagnosis is not yet possible. A region on chromosome 10 has been shown to be the most significant portion of our genome associated with AMD. However, the exact protein associated with AMD has not yet been identified. The preponderance of evidence, however, points to one of two proteins, LOC387715 and HtrA1. We hypothesize that the AMD gene on chromosome 10 is one of these two proteins. However, it is not possible to use genetic or statistical techniques to determine which protein is more likely to be associated with AMD. We will use human donor eyes to determine where these proteins are located and to determine which tissues in the eye express these proteins. We will also extract these proteins from human retinal tissue and cells to study their size and quantity. Through looking at where these proteins are expressed and located inside the back of the eye, where AMD occurs, we hope to obtain evidence that will determine which protein is associated with AMD. This will help us in the future to develop assays to determine which individuals are most likely to get AMD and to develop treatments that will better alleviate this devastating disorder.
Robin L. Seitzman, Ph.D.
University of California, Los Angeles
Los Angeles, CA
Project: Single Nucleotide Polymorphisms and AMD in Older Women
$100,000
Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in persons 65 years of age and older in the developed world. The cause of AMD is not known; however, it is believed that a combination of genetic and environmental factors is responsible for the majority of cases. Therefore, studies involving genes relevant to eye tissues and function, and determining if their effects are modified by the presence of other AMD risk factors such as smoking. This may reveal important information regarding the cause of this important disease. Some of our preliminary research suggests that bone disease and AMD may have common risk factors. Therefore, genes relevant to bone disease and metabolism may be associated with AMD risk. Using data from the Study of Osteoporotic Fractures, the goals of our study are to determine whether variations in 15 genes related to bone metabolism and expressed in eye tissues are associated with incident AMD in women 75 years of age and older, and whether genetic effects may be modified by environmental risk factors for AMD such as smoking, nutritional factors, or reproductive hormone exposures.
Allen Taylor, Ph.D.
Tufts University
Boston, MA
Project: Carbohydrate, Dietary Patterns and AMD rick in 2 Cohorts
$100,000
Age related macular degeneration (AMD) is due to damage to the most sensitive portion of the retina, the macula. It is in this zone that light information is received and converted to signals that are then interpreted by the brain. Estimates vary for prevalence of AMD, but it appears that over 15% of the elderly are subject to some visual loss due to AMD. With the aging of our population, along with increasing diabetes and obesity, this proportion is sure to grow significantly. It is the major cause of non remediable blindness. The personal, societal, and public health ramifications of such an epidemic are horrific. We obtained preliminary evidence that limiting dietary simple carbohydrates is associated with prolonged retina function and less indication of macular damage. Since at present there are no intervention trials which specifically test the hypothesis that limiting simple carbohydrates is associated with prolonged retina function, we seek to use data from existing large well executed ophthalmic/nutritional/epidemiologic studies to test the hypothesis. had we set out to do this work from the beginning it would cost many millions of dollars. By using existing data sets, we can accomplish this mission with a fraction of the cost. This grant will help us accomplish this objective.
Heping Xu, Ph.D.
University of Aberdeen
Foresterhill, Aberdeen, UK
Project: Retinal Pigment Epithelial Cells and Complement
$100,000
Age-related macular degeneration (AMD) is the largest cause of untreatable blindness in developed countries. How the disease is started is not known. Recent evidence suggests that patients who carry variants of certain gene (namely complement regulatory factor H (CFH) gene) are at higher risk of developing AMD, whereas another gene (namely complement factor B (CFB) gene) variation can reduce the risk of AMD. The products of these two genes are CFH and CFB proteins, which are both important in complement activation (a kind of inflammation). CFH/CFB proteins are normally produced in the liver and distributed in the blood stream. Patients with AMD usually have no other diseases related to CFH or CFB dysfunction apart from the eye. We speculate that these genes also are active in the eye with local protein productions, this may serve as a regulatory system to prevent unwanted inflammation. When these genes are not functioning properly as in some variants of the genes then AMD might develop due to damage from local inflammation. The project is to investigate how CFH/CFB protein production is controlled in the eye in normal and disease conditions. It will help us to identify factors that are responsible for AMD development, and develop new treatments.
Caroline J. Zeiss, Ph.D.
Yale School of Medicine
New Haven, CT
Project: Interaction of diet and genotype in the pathogenesis of AMD
$100,000
Age-related macular degeneration is the predominant cause of vision loss in adults over 65. There is no single cause for this disease, and it results from complex interactions of genetic predisposition and environmental influences. Consequently, it is difficult to predict, and to treat. Lack of effective treatment stems from both the complexity of the disease, and lack of good animal models in which to study it. We have been able to obtain a mouse model that carries a mutation in an important macular degeneration gene - Factor H. Using this mouse as the basis of our experiments, we will superimpose additional mutations (ApoE and CCr2) and environmental conditions (high fat diet). We expect that these interventions hasten onset of AMD in mice. We will also determine whether mice carrying a mutation in Tlr4, a gene that has recently been associated with AMD, develop AMD-like lesions after normal or high fat feeding. The intent of this is to develop a robust early onset mouse model of AMD for therapeutic testing. These experiments also provide insight into how diet interacts with predisposing genetic burden to create AMD pathology. Understanding these relationships will enhance the capacity of the clinician to council at-risk patients.
FUNDING PERIOD: APRIL 1, 2006 – MARCH 31, 2008
Steve Abcouwer, Ph.D.
Pennsylvania State University College of Medicine
Hershey, PA
Project: Effect of Mutant Fibulin Expression on RPE Cell Function
$100,000
A single genetic mutation in the fibulin-3 gene causes inherited early-onset macular degenerative disease known as Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD). Similar mutations in other fibulins (5 and 6) are linked to age-related macular degeneration (AMD). These mutations cause the expression of abnormal forms of fibulin proteins. How these abnormal proteins contribute to macular degeneration is unknown. He provides a testable hypothesis of how expression of a mutant protein might cause retinal pigment epithelial (RPE) cell dysfunction leading to macular degeneration. Expression of fibulin-3 mutant protein lead to accumulation of this protein in an intracellular organelle called the endoplasmic reticulum (ER), causing stress to this organelle. The hypothesis that the expression of mutant fibulin proteins compromises the ability of RPE cells to perform one of their primary functions, swallowing and processing of outer segments that are shed from photoreceptor cells. Evidence suggests that the rate of outer segments shedding and the ability of the RPE to remove and process the outer segments are key factors in the progression of AMD. The proposed studies would expand the understanding of these vital RPE functions, and could point the way to AMD treatments that act by alleviating protein aggregation.
Qiuyun Chen, Ph.D.
Cleveland Clinic Foundation
Cleveland, OH
Project: Identification of Human Retinal Lutein Binding Proteins
$200,000
The long-term goal of this project is to study the molecular basis for therapeutic manipulation of lutein levels in the retina in order to treat age-related macular degeneration (AMD), the leading cause of incurable blindness in the western world. Lutein is one of the few carotenoids that are selectively accumulated in the human macula. Low concentrations of lutein in the retina have been found to correlate with a high risk of developing AMD. However, the exact molecular mechanisms underlying the protective function of carotenoids are unresolved. One reason this problem persists is the lack of knowledge of how and why lutein is selectively accumulated in the macula. Dr. Chen’s hypothesis is that specific binding proteins facilitate the transport and retention of lutein in the retina. To test this hypothesis, she will identify lutein binding proteins from human retina by searching for genes that when expressing will produce proteins that specifically bind lutein. Once the gene(s) are identified, she will determine what type of proteins they are and whether their distribution in the retina correlates with the lutein distribution pattern.
Xi-Qin Ding, Ph.D.
University of Oklahoma Health Sciences Center
Oklahoma City, OK
Project: Molecular Defects of the Cone CNG Channel Mutations
$100,000
Cone vision mediated by the photoreceptor cyclic nucleotide-gated (CNG) channel activation is essential for the central and color vision and vision acuity. The proper channel structure is essential for the channel function. Indeed, over 60 mutations in genes encoding the channel proteins have been linked to progressive cone dystrophy, macular degeneration, and various forms of color blindness in humans. Among these mutations, the R277C, R283W, R436W, and F547L substitution account for 42% of all detected mutant CNG A3 gene. Dr. Ding’s hypothesis is that the mutations in the channel protein interfere with the proper channel structure, which in turn hampers the channel function. It is overt that elucidating the pathogenesis of mutation is essential for development of the therapeutic strategies. Thus, the main goal of this proposal is to establish the molecular basis of the channel dysfunction caused by the mutations. The first specific aim is to explore the channel structural defects in the R277C, R283W, R436W, and F547L mutants and the second specific aim is to determine the functional deficiency of the mutant channels. The long-term goal of this study is to develop the therapeutic strategies for cone dystrophy, color blindness, and macular degeneration related to the cone CNG channel mutations.
Elia Duh, M.D.
Johns Hopkins
Baltimore, MD
Project: Regulation of Angiogenesis in CNV by Akt/Forkhead
$200,000
The major reason for severe visual loss in AMD is choroidal neovascularization (CNV), or the formation of abnormal new blood vessels underneath the retina. The goal of this project is to pursue a new direction in CNV research by investigating the role of an intracellular signaling pathway that may play a critical role in the formation of CNV. The project will be focused on the Akt pathway, which is thought to play a critical role in angiogenesis and appears to be particularly important for endothelial cell survival; therefore inhibition of this pathway may be a clinical strategy for causing regression of existing CNV. It is the overall hypothesis that the Akt signaling pathway plays a major role in mediating the effects of pro- and anti-angiogenic factors (including VEGF and PEDF) in regulating CNV. The specific research in this application is intended to investigate/demonstrate the importance of the Akt signaling pathway in CNV, in order to identify a new therapeutic target. This research will investigate the importance of the Akt pathway in choroidal endothelial cell survival (using cultured choroidal endothelial cells) as well as in a mouse model of CNV. The long-term goal of this research is to gain an enhanced understanding of CNV and provide new molecular targets for the pharmacologic treatment of AMD.
Michael Gorin, M.D., Ph.D,
University of Pittsburgh
Pittsburgh, PA
Project: Linkage and Association Studies for Macular Degeneration
$150,000
Age-related macular degeneration (ARM) is a major cause of vision loss in the elderly. It is thought that smoking and diet may contribute to the risk of developing the condition but it is clear that heredity plays a major role. Variations in two genes, CFH and PLEKHA1/LOC387715, have been found to strongly contribute to the risk of developing ARM, but there are additional genes that probably influence a person’s chances of having this condition and how they will progress to vision loss. Dr. Gorin is investigating the genetic variations that contribute to ARM so that he can eventually understand the causes of this complex condition. He studies the genetic variations that are shared among ARM-affected individuals within families as well as compare the frequencies of genetic variations in ARM-affected individuals with those in unaffected persons who are matched in age, gender, and exposures. His long-term goals are to develop new preventive therapies that can slow or halt the development of this disease and to be able to provide these treatments to those who are at greatest risk before they experience vision-threatening changes.
Jeffrey Gross, Ph.D.
University of Texas at Austin
Austin, TX
Project: A Genetic Model of RPE Dysfunction in ARMD
$150,000
In patients with the dry form of age-related macular degeneration (ARMD), a substance called drusen builds up in cells of the retinal pigment epithelium (RPE) – the pigmented layer at the back of the eye. Drusen poisons RPE cells by inhibiting their ability to degrade protein and lipid components of photoreceptors – the light sensitive cells of the retina. Normally, RPE cells help to maintain the survival of photoreceptors by continually removing their tips, which have accumulated cellular damage over time. Dr. Gross will study the mechanisms that RPE cells utilize to facilitate photoreceptor degradation, focusing on a protein complex called the vacuolar ATPase that is necessary for degradative processes in other cell types. Dr. Gross predicts that mutations in the vacuolar ATPase complex lead to ARMD in humans. To test this prediction, Dr. Gross will analyze the effects of vacuolar ATPase mutations in zebrafish, an animal model system in which human diseases can be studied. Zebrafish vacuolar ATPase mutants show severe ARMD-like pathologies in their eyes and are therefore an excellent animal model system in which ARMD progression can be further understood.
Marc Kantorow, Ph.D.
Florida Atlantic University
Boca Raton, FL
Project: Methionine Sulfoxide Reductase in Retinal Function
$100,000
Upon aging, many types of protein damage accumulate and this accumulation is believed to be a major factor in many age-related diseases. Oxidation of the amino-acid methionine is one of the most common. Unlike many other types of protein damage, methionine oxidation can be repaired by a unique enzyme called MSRA. Dr. Kantorow has found that MSRA is important for protecting retinal cells and that loss of this enzyme in mice causes loss of photoreceptors required for visual function. He has also found that this enzyme is preferentially found in the macula. This project hypothesizes that MSRA is critical for retinal function and that loss of MSRA activity could contribute to age-related macular degeneration. Dr. Kantorow proposes to determine how deletion of MSRA effects the retina and visual function of mice who lack the enzyme relative to normal mice. These studies are likely to provide important insight towards understanding age-related macular degeneration and may provide clues towards developing therapies for this disease.
Nancy Mangini, Ph.D.
Indiana University School of Medicine-Northwest
Gary, IN
Project: Role of Melanin and a Novel Na:Ca:K Exchanger in AMD
$200,000
Age-related macular degeneration (AMD) is the leading cause of impaired vision among the elderly in the U.S. Progression of this condition to irreversible blindness is more likely to occur in Caucasians than in Blacks. This finding has led to the suggestion that having more eye pigmentation (melanin) protects against aging changes that cause vision loss in advanced AMD. Dr. Mangini proposes that a newly discovered protein, called NCKX5, is necessary for pigment synthesis and that impaired functioning of this protein will predispose to development of advanced AMD. This project will examine the possible role of this novel calcium transport protein in the development of AMD. The activity of NCKX5 in eye cells from Black versus Caucasian donor eyes will be examined. In addition, the project will determine if an experimental animal, the zebrafish mutant, golden, which lacks pigment due to mutation of NCKX5, exhibits eye changes like those seen in human AMD. This study will open up new avenues of research into the causes of AMD and will establish whether a powerful animal model, the zebrafish mutant, golden, can be used to rapidly and inexpensively test new drugs and clinical protocols to treat AMD.
John O’Brien, Ph.D.
The University of Texas Health Science Center at Houston
Houston, TX
Project: Physiological Uncoupling of Cone Gap Junctions
$200,000
Photoreceptors are joined to each other by gap junctions, channels that permit exchange of small molecules between adjacent cells. During cell death, such as occurs in macular degeneration, death-promoting factors may pass through gap junctions to adjacent cells and trigger death in otherwise healthy adjacent photoreceptors. This process can speed the progression of disease and hasten vision loss. Treatments that close these gap junctions may delay the progression of disease. This project will examine the physiological mechanisms that close cone-cone gap junctions. By studying biochemical properties of the cone photoreceptor gap junction protein, connexin35, Dr. O’Brien can estimate the functional state of the gap junctions. He will now use these studies to identify the signaling pathways that change the functional state of cone gap junctions. This information will be used to develop pharmacological interventions to close cone gap junctions, reducing the exchange of small molecules between photoreceptors. It is hoped that these studies will identify drugs that can be used to close cone gap junctions selectively. Such drugs could provide a treatment strategy that is complementary to existing treatments for macular degeneration by reducing the rate at which the degeneration spreads.
David Pepperberg, Ph.D.
University of Illinois at Chicago
Chicago, IL
Project: Nanoscale Modulators of Retinal Postsynaptic Receptors
$100,000
In the normally functioning retina, visual signals initiated in the rod and cone photoreceptor cells are transmitted to other nerve cells of the retina called "post-photoreceptor" cells. Patients with retinal degenerative diseases such as age-related macular degeneration (AMD) have deteriorating rods and cones. However, there is reason to believe that in certain patients, post-photoreceptor retinal nerve cells remain capable of functioning. Functional post-photoreceptor cells suggest an opportunity to restore sight in AMD patients. The idea is to develop molecular structures (tiny machines) that would interact with specific proteins on the surfaces of these cells and stimulate them in response to light that enters the eye. The molecular structures that are envisioned, once introduced into the patient's diseased retina, would bind tightly to the post-photoreceptor cells and initiate visual signals, thereby bypassing the deteriorated rod and cone cells. The overall goal of the project is to design and construct structures that can achieve this challenging objective in molecular bioengineering and nanotechnology. These molecular machines could serve as a therapy for AMD, and additionally could provide a model for treating other neurodegenerative diseases.
Enrique Rodriguez-Boulan, M.D.
Weill Medical College of Cornell University
New York, NY
Project: Drug Screening to Modulate RPE Lysosomal Dynamics in AMD
$100,000
Age-related macular degeneration (AMD) is a disease that stems from a variety of factors and exhibits several different features. This makes it difficult to gain the insight into the disease process that is essential for designing drug therapies. It is now believed that the primary insult in AMD occurs in cells of the retinal pigment epithelium (RPE) that underlie the photoreceptors or the light-sensing cells of the retina. While researchers have shown that a by-product of the visual cycle known as “A2E” may damage the RPE, a complete understanding of how this occurs is still lacking. It is known that A2E accumulates in organelles called lysosomes which are the degradative compartments of the cell. Work from the laboratory has shown that A2E interferes with lipid metabolism in the RPE. The research proposed in this application aims to use a powerful technique called high-throughput screening to examine the potential of 20,000 chemical compounds to either remove A2E from the cell or restore normal lipid metabolism in the RPE. It is the hope that this research will not only identify potential drug candidates but also open new lines of inquiry into understanding how vision loss occurs in AMD.
FUNDING PERIOD: APRIL 1, 2005 – MARCH 31, 2007
Jiankang Liu, Ph.D.
Children’s Hospital
Oakland Research Institute
Oakland, CA
Project: Mitochondrial Protective Compounds: Protection of Retina
The retinal pigment epithelium (RPE) is a single layer of epithelial cells located behind the neutral retinal and at the back of the eye. RPE cells are particularly susceptible to oxidative damage and mitochondria are one of the primary targets of oxidative damage in RPE cells. Dr. Liu believes mitochondrial damage due to oxidative stress in RPE contributes to the retinal degeneration observed in AMD. The proposed study of mitochondrial oxidative injury and mechanisms of mitochondrial protection in RPE cells could lead to a better understanding of the mitochondrial decay mechanisms involved in RPE damage observed in AMD and the use of mitochondrial protective compounds to prevent and treat RPE degeneration and ultimately, AMD. If his experiments are successful they may furnish a low cost and easily implemented way to prevent or counteract the damage from AMD.
Jiyang Cai, Ph.D.
Vanderbilt University Medical Center
Nashville, TN
Project: Extracellular Redox Control of Cell Survival Pathways in the RPE
An important pathological change of AMD is the degeneration of the retinal pigment epithelial (RPE) cells. Previous studies have demonstrated that oxidative stress contributes to the degenerative process of the RPE, and that risk factors of AMD, such as aging and smoking, are also associated with increased systemic oxidative stress. Dr. Cai intends to characterize how a newly identified protein, FKBP38, may function to protect the RPE against oxidative stress. Although previous studies have shown FKBP38 to be a potent inhibitor of cell death, its role in AMD has never been studied.
James Handa, M.D.
Johns Hopkins University
Wilmer Eye Institute
Baltimore, MD
Project: Advanced Glycation Endproduct Mediated Cholesterol Deposition in Bruch’s
Membrane
When looking at AMD eyes under the microscope, the most distinguishing change is basal deposits, or accumulations of material within Bruch’s membrane, a specialized scaffold upon which the retinal pigment epithelium (RPE) attaches. Prior to basal deposit formation, cholesterol (fat) is deposited into Bruch’s membrane. Dr. Handa believes that understanding how cholesterol gets deposited into Bruch’s membrane will help researchers to design targeted new treatments that prevent the onset of AMD or slow the inevitable progression from early to late disease.
H. Criss Hartzell, Ph.D.
Emory University School of Medicine
Atlanta, GA
Project: RPE Cell Volume Regulation by Bestrophins
There are a number of inherited forms of macular degeneration which may provide insight into age-related macular degeneration. One inherited form of macular degeneration is caused by a gene (bestrophin) that makes a protein that is a chloride ion channel. Chloride ion channels are conduits for movement of chloride ions between the inside and outside of the cell. Although it is not understood how the dysfunction of a chloride ion channel can cause macular degeneration, Dr. Hartzell plans to use genetic models to explore the role that chloride channels play in the function of the retina. Dr. Hartzell believes that the function of these channels may be to regulate the volume of the cell. This is important because a lack of volume regulation causes cells to burst.
Breandán Kennedy, Ph.D.
University College Dublin
Dublin, Ireland
Project: Novel Cone-Specific Genes – Therapeutic Targets for Macular
Degeneration
Vision is possible because of the abundance of specialized structures known
as cone photoreceptor cells, located in the macula. Macular degeneration causes
these cones to die and results in severe visual handicap and blindness in affected
individuals.
If a means to help cone photoreceptors live longer can be identified, this
will significantly improve the quality of life of affected patients. It is
likely that factors involved in the initial formation of cones during development,
and products that are specifically found in cone photoreceptors, will in turn
promote cone survival. Once these factors have been identified, the long-term
goal will be to determine if the addition of these factors is therapeutically
beneficial to humans affected by macular degeneration by slowing or preventing
the onset of blindness.
Heidi Vollmer-Snarr, Ph.D.
Brigham Young University
Provo, UT
Project: Isolation of Novel Compounds Involved in RPE Atrophy
AMD is a disease in which the macula, the central part of the retina of the eye, loses cells which cannot be replaced. This cellular damage is believed to be responsible for the loss of vision. The primary goal of the Dr. Vollmer-Snarr’s research efforts is to more completely identify the specific chemical components of the macula that are being damaged and may cause AMD. Chemical composition of the macula strongly suggests that unknown compounds related to the known damaging agent are present. These other components may provide a missing link in our understanding of AMD and other macular diseases. The long-term objective of this project is to provide new insight in order to develop preventative and therapeutic strategies for AMD and other retinal degenerative diseases.
FUNDING PERIOD: AUGUST 1, 2004 - JULY 31, 2007
(Funding for this project will be reflected in the 2005 Annual Report)
Nicolas G. Bazan, M.D., Ph.D.
Louisiana State University Health Sciences Center
New Orleans, LA
Project: Signaling in RPE (Retinal Pigment Epithelial) Cell Survival
Dr. Bazan will be examining human retinal pigment epithelial (RPE) cells in lab cultures while simulating conditions that occur in the eye with age-related macular degeneration. RPE cells form an important membrane separating the retina’s light-sensitive rod and cone cells from another membrane, called Bruch’s membrane. In the early form of the disease, called “dry” macular degeneration, the RPE cells slowly degenerate along with the cells of the retina. When macular degeneration becomes advanced, as in the “wet” form of the disease, bleeding from abnormal blood vessels can burst through Bruch’s membrane and the RPE cell layer, damaging or destroying the fragile rods and cones. All vision loss due to this cellular damage is irreversible.
The specific focus of Dr. Bazan’s study will be to identify signaling chemicals that cue the RPE cells whether to survive or die, and he hopes to identify the agents that help RPE cells survive under disease conditions. The discovery of a protective agent for RPE cells could lead to a drug therapy that could be used early in the course of age-related macular degeneration, before too much damage has occurred.
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