FUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2009

Michael G. Anderson, Ph.D.
The University of Iowa
Iowa City, IA
Project:Genetics of Central Corneal Thickness in Mice
90,000

The cornea is the outermost covering of the eye.  Given the importance of the cornea to vision, it is somewhat surprising that the cornea exhibits vast person-to-person variability, especially regarding its overall thickness (referred to as central corneal thickness, CCT). Recently, it has become clear that differences in CCT are more than a mere anatomical curiosity. CCT strongly associates with several ocular diseases, particularly glaucoma.  The Ocular Hypertension Treatment Study (OHTS, a large, multicenter, prospective clinical glaucoma study) recently found that a thinner CCT predicts the development of primary open angle glaucoma. The pathophysiological reason for this association remains unknown. Our experiments offer an innovative approach that will allow CCT to be studied at the molecular level using experiments with mice. Knowing the genes that influence CCT, even in mice, will immediately suggest new mechanistic hypotheses that can be carried back into human studies.

Our work also addresses an important health disparity issue that exists among patients with glaucoma.  Advancing age and elevated intraocular pressure are two well known risk factors for developing glaucoma. Race is another. Both the incidence of glaucoma and the incidence of thin corneas are much more common among African Americans than other ethnicities. For unknown reasons, African Americans with glaucoma have on average more severe disease that is more resistant to treatment in comparison to patients of other ethnicities. The reason for these associations may in part reflect the biological connections that link CCT and glaucoma. Our studies in mice offer an innovative approach for identifying molecules influencing CCT and experimentally testing their relevance to glaucoma.

Ultimately, results of these studies will contribute to an improved understanding of the risk factors that contribute to glaucoma, with the long term goal being the development of improved therapies and outcomes for all people affected by glaucoma.

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Dong Feng Chen, M.D., Ph.D.
Schepens Eye Research Institute
Boston, MA
Project: Astroglial Contributions to Glaucoma
$90,000

Glaucoma is a leading cause of blindness in the world and affects an estimate 3 million Americans. In most cases, glaucoma is caused by elevated intraocular pressure that damages the optic nerve and eventually leads to death of retinal ganglion cells (cells that extend nerve fibers to form the optic nerve). Current therapy for glaucoma is directed at lowering intraocular pressures, but very often, it fails to prevent the progressive neuron and vision loss associated with the disease. Therefore, finding ways that protect the optic nerve and c from injury are crucial to the development of more efficacious treatment for glaucoma. Retinal astroglial cells are supporting cells of the retina. Accumulating evidence suggests that when these supporting cells respond to nerve injury, they induce detrimental effect on the nerve and retinal ganglion cells, thus, may contribute critically to the development and progression of the disease. In the present application, we hypothesize that responses of these supporting cells are directly responsible for glaucoma-induced optic nerve damage and retinal ganglion cell death by producing neurotoxic agents, triggering inflammation, and generating an inhospitable environment. The objective of this research plan will define the functional roles of these supporting cells in optic nerve and retinal ganglion cell damage in glaucoma and eventually, design drugs that prevent neuronal damage and vision loss by targeting to the function of these cells. We have proposed three Specific Aims:

• Aim I will investigate the functional roles of these supporting cells in optic nerve and retinal ganglion cell degeneration in a glaucoma mouse model as well as test the effect of a potential chemical that can eliminate the detrimental effects of the supporting cells.
  
  
• Aim II will further prove the concept by defining the roles of these supporting cells using a genetically engineered mouse models.
  
  
• Aim III will take advantage of the new technology of cDNA microarray to determine the molecular basis underlying the detrimental effects of the supporting cells after nerve injury.  Results derived from this study will provide important information for developing new therapeutic strategies to treat glaucoma and other brain and optic nerve damage.

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Dharamainder Choudhary, Ph.D.
University of Connecticut Health Center
Farmington, CT
Project: Mechanistic Effects of CYP1B1 Variations in POAG
$90,000

Our group first (1997) linked the presence of CYP1B1 mutations with Primary Congenital Glaucoma (PCG) phenotype in patients. Recently, CYP1B1 mutations have also been shown in other eye diseases with anterior chamber abnormalities and in juvenile and adult onset Primary Open Angle Glaucoma (POAG). This involvement in a wide spectrum of eye diseases suggests a crucial role of CYP1B1 in maintaining the physiology of the eye during embryonic to adult stages of life. We hypothesize that CYP1B1 may act as a key factor, which modulates the effect of other known POAG causative genes e.g., myocilin, optineurin and WDR36. We have a number of genomic DNA samples of glaucoma subjects who have previously been shown to be positive for mutations in one of the above-mentioned genes. We will screen for the presence of CYP1B1 mutations in these glaucoma families. The anticipated CYP1B1 mutations observed will be functionally tested by our previously established biochemical and molecular protocols. The positive co-existence of mutations in CYP1B1 and other known glaucoma genes will aid in establishing a common protocol for examining CYP1B1 mutations in individuals with family background of possessing mutations in either myocilin, optineurin or WDR36. This will help in early identification of the individuals who are at higher risk of developing glaucoma phenotype at early stages of adult life.

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Haiyan Gong, M.D., Ph.D.
Boston University School of Medicine
Boston, MA
Project: Outflow Area and Its Role in Glaucoma Pathogenesis
$90,000

Glaucoma is typically associated with elevated intraocular pressure (IOP) caused by increased aqueous outflow resistance. In previous studies of bovine eyes, we found that the area available for outflow increases when IOP and outflow resistance decreases, suggesting a relationship between available area for outflow and outflow resistance. The morphological correlation of reduction in the area available to outflow, with increasing IOP, seems to be related to a progressive collapse of the Schlemm’s canal and a previously unrecognized, progressive herniation of the inner wall and the JCT into the collector channel ostia. A similar herniation of the inner wall into the collector channel ostia was also seen when the eyes were fixed even at 0 mmHg raising the prospect that initially reversible herniations can become irreversible. We hypothesize that the herniations we have documented will be found to be reversible in eyes without glaucoma but can become irreversible, leading to increased outflow resistance and IOP. The results of this study will help us to better understand glaucoma pathophysiology and will also better direct us to the anatomical sites where the pathological resistance resides.

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Xuri Li, Ph.D.
NIH/NEI
Bethesda, MD
Project: Neuroprotection of Retinal Ganglion Cells by VEGF-B
$88,920
 
Glaucoma is the most prevalent form of adult optic neuropathy characterized by the degeneration and death of the retinal ganglion cells (RGCs). Molecules with neuroprotective effect on the endangered RGCs are therefore much desired to preserve and rescue the RGCs and thus the vision of glaucoma patients. This research proposal is therefore designed to test in vivo the neuroprotective effect of one such candidate molecule, the vascular endothelium growth factor B (VEGF-B), and to further characterize the molecular and cellular mechanisms underlying. VEGF-B has been shown to be a critical neuroprotective factor in the brain. Our current work has shown that VEGF-B may play important roles in the retina. Based on our preliminary studies, we hypothesize that VEGF-B may have a neuroprotective effect on the retinal ganglion cells. To test this hypothesis, we will use multiple approaches and methods, including both normal and VEGF-B transgenic mice, both protein and gene transfer, both gain and loss of function analysis, to investigate the neuroprotective effect of VEGF-B on retinal ganglion cells in vivo. The outcome of this study may lead to possibilities of novel therapy for glaucoma patients and more insight into the course of glaucoma.

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Brian A. Link, Ph.D.
Medical College of Wisconsin
Milwaukee, WI
Project: Identifying Glaucoma-Promoting Genes Using Zebrafish
$90,000
(This project is additionally supported by the Glaucoma Research Foundation, San Francisco, California)

Glaucoma is a leading cause of blindness world-wide and yet our understanding of the genetic basis of this neurodegenerative disease remains largely unknown.  One reason for this is that glaucoma is really a collection of diseases and each form is thought to be caused by mutations in multiple genes.  The main goal of this study is to identify genes that cause ganglion cell degeneration when intraocular pressure (IOP) is elevated, a key feature of many forms of glaucoma.  Using zebrafish that show elevated IOP with out associated ganglion cell degeneration, we will screen for ‘interacting’ mutations that lead to injury response pathways in retinal ganglion cells and eventually cause blinding degeneration.   Zebrafish are ideal for these studies because they share similar ocular anatomy, physiology and genetics as humans.  In addition, zebrafish can be raised in very large numbers at modest cost, facilitating complex forward genetic endeavors.   Once the key genes for glaucoma are identified, genetic tests can be developed and ultimately, research for targeted therapies can begin.

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K. Saidas Nair, Ph.D.
The Jackson Laboratory
Bar Harbor, ME
Project: Determining Immune Components of DBA/2J Glaucoma
$90,000

Harmfully high intraocular pressure (IOP) is a major risk factor for glaucoma. Pigment dispersion syndrome (PDS) is a common condition that deposits abnormally liberated iris pigment into the pathway that drains the ocular fluid from the eye.  In some cases, the deposited pigment harms the drain resulting in high IOP and glaucoma. Not all PDS progresses to high IOP and glaucoma suggesting that the pigment itself is not sufficient to induce high IOP. DBA/2J mice have pigment dispersion, mild intraocular inflammation and develop high IOP. We hypothesize that the pigment dispersion and inflammation cooperate to induce the high IOP in these mice. To test this hypothesis, we will use genetically altered DBA/2J mice that are devoid of a subset of immune cells that mediate inflammatory responses. We will determine if the mice develop high IOP and glaucoma in the absence of these cells. Also, we will test if a specific DBA/2J gene predisposes to the inflammation and thereby confers susceptibility to IOP elevation. Our studies may suggest new therapies to prevent progression from PDS to glaucoma by reducing inflammatory responses.

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Kwok-Peng Ng, Ph.D.
Cleveland Clinic Foundation
Cleveland, OH
Project: Glaucoma Biomarker Discovery and Pathogenetics
$90,000

Glaucoma is a group of eye diseases that damages the optic nerve and result in blindness if left untreated. The most common form is primary open-angle glaucoma (POAG). POAG affects over 3 million Americans, a majority of whom do not know they have it. There is currently no cure for glaucoma. We believe that molecular markers exist in the blood of individuals susceptible to developing glaucoma. These molecules are small fragments of proteins that arise from breakdown of proteins during normal cellular functions in the body. Sometimes the levels of certain molecules in the blood change when a person gets sick. The identification of these molecular markers or “biomarkers” will let doctors identify those at risk before clinical evidence of the disease. More importantly, these biomarkers could lead to new therapies for glaucoma. We will use instruments known as mass spectrometers to identify biomarkers in blood samples from individuals with POAG. These biomarkers will be analyzed to ensure they are specific to glaucoma and hence useful for the development of diagnostic tests and new drugs. The long term goals of our research are to develop 1) a blood test for early detection and 2) new treatments for this debilitating disease.

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Robert W. Nickells, Ph.D.
University of Wisconsin-Madison
Madison, WI
Project: Cell Based Neurotrophin Therapy for Glaucoma
$90,000

Glaucoma is a blinding disease characterized by the progressive loss of retinal ganglion cells.  One major line of therapeutic intervention being developed for glaucoma is the introduction of growth factors that can prevent the death of the ganglion cells.  Two major hurdles in this area of investigation is that we have not been able to deliver more than one or two factors at a time and we can not deliver them for long enough periods.  Evidence suggests that the most effective treatment would be the delivery of multiple factors for periods of several months to years.  A possible solution to these problems is the use of progenitor cells.  These cells are similar to stem cells in that they are undifferentiated and can self renew or divide in culture.  These cells can be used as transplants in damaged nerve tissue, where they can infiltrate the regions of damage and make contact with living neurons.  Another advantage of these cells is that we can alter them in the laboratory to express and secrete the complex mixture of growth factors that ganglion cells need to survive.  Once transplanted into the eye, we hypothesize that they will make contact with surviving ganglion cells and provide them with the critical growth factors needed for survival.  Lastly, we expect that these cells will provide the growth factor support for extended periods of time without any additional treatment.  Using progenitor cells for this “cell based therapy” is a relatively new concept for treating glaucoma.  This proposal is designed to address some of the fundamental questions we need to answer to pursue this line of therapy.  Among the questions we will address are:

• Where do the cells go when injected into the vitreous cavity - do they penetrate the retina and make contact with the target ganglion cells?
  
  
• How long do the cells survive in the retina?
  
  
• Can these cells attenuate the rate of ganglion cell loss when engineered to secrete a single growth factor known to promote ganglion cell survival?

To answer these questions, we propose to study their effects on mice that spontaneously develop glaucoma as they age.  If successful, we propose to extend these studies by altering these cells further to secrete a potent mixture of growth factors required for maximal ganglion cell survival.

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Colm O'Brien, M.D.
Mater Misericordiae Hospital
Dublin, Ireland
Project: Modulation of Lamina Cribrosa Matrix Remodeling in POAG
$90,000

This project intends to test the hypothesis of that the use of novel anti-fibrotic therapies will reduce the damage done in glaucoma to the retinal ganglion cells thereby alleviating the resultant loss of vision. At present glaucoma represents the most common form of irreversible blindness in the western world. The exact causes of the different types of glaucoma are not fully understood but in one common form, primary open angle glaucoma it is believed that mechanical strain induced by elevated intra-occular pressure plays a part. This causes changes in the connective tissue of the lamina cribrosa, which is where the optic nerves exit the eye. Previous evidence has shown that soluble growth factors such as the TGF- family can affect the extracellular composition of this tissue. By modulating the expression of the TGF- family we hope to change the connective tissue composition of the lamina cribrosa and thereby reduce the damage to the retinal ganglion cells and reduce loss of visual function.

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Noorjahan Panjwani, Ph.D.
Tufts University School of Medicine
Boston, MA
Project: Identification of TM Cell Markers
$90,000

Glaucoma is the second leading cause of blindness in the world.  Nearly 2.5 million individuals in the US and 70 million worldwide are affected by this blinding disease.  Elevated IOP due to reduction in aqueous outflow facility is a major causal risk factor. In humans, the aqueous outflow pathway is constituted of Schlemm's canal (SC) lined by its endothelial cells, and trabecular meshwork (TM)  which is divided into the corneoscleral (CS) portion with its endothelial-like TM cells and the juxtacanalicular (JCT) portion with its fibroblast-like TM cells.  The functional differences and relative importance of the different cell populations residing in the outflow pathway is a subject of great debate in the field.  While the three cell types of the outflow pathway can be readily distinguished in tissue sections based on distinct morphology, no specific markers have been identified that distinguish JCT and CS cells from one another. Clearly, for the analyses and interrogation of each cell type of the aqueous outflow pathway with respect to its role in the outflow resistance and the pathogenesis of glaucoma, availability of robust markers that would permit preparation of pure cultures of each cell type is a prerequisite. In this application we propose studies to identify differential markers of the three distinct cell types of the aqueous outflow pathway using the most modern, state of the art techniques. It is our hope that characterization of gene expression patterns of distinct cell types of the outflow pathway will lay the foundation for research by novel, more accurate approaches for understanding the pathogenic mechanisms of glaucoma.

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Carla J. Siegfried, M.D.
Washington University
St. Louis, MO
Project: Aqueous Humor Oxidative Stress Markers in Glaucoma
$90,000

Glaucoma, the second leading cause of blindness worldwide, is characterized by damage to the optic nerve which transmits visual information from the eye to the brain.   Most cases are associated with increased eye pressure and decreased outflow through the drainage meshwork in the front of the eye.  Current theories suggest that this age-related disease, as well as other eye conditions like cataract and macular degeneration, may be related to oxidative damage, toxic effects of excess oxygen forming harmful molecules called free radicals.  Our proposed study will examine the aqueous humor, the fluid in the front of the eye, of patients who are undergoing eye surgery. We will measure both a byproduct (hydrogen peroxide) and a protectant (ascorbic acid) of oxidative damage, as well as oxygen levels in different parts of the front of the eye.  By aiding in further understanding of this oxidative mechanism of glaucoma damage, it may lead to innovative therapies for this devastating condition.

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Donald J. Zack, M.D., Ph.D.
Johns Hopkins University
Baltimore, MD
Project: Role of CHOP and ER stress in RGC Degeneration
$90,000

Glaucoma is a major cause of vision loss. It is the second moss common cause of blindness worldwide. In glaucoma, decreased vision is caused by the injury and death of retinal ganglion cells (RGCs), the cells that transmit visual information from the eye to the brain. All current forms of glaucoma treatment (drugs, laser treatment, and surgery) act by lowering the pressure within the eye. Although pressure lowering can be helpful, RGC loss can continue even after pressure reduction. Greater understanding of the molecular mechanisms underlying retinal ganglion cell (RGC) loss will likely make possible the development of more effective diagnostic and treatment strategies. In the work proposed in this application we will explore the molecular mechanisms that actually induce the death of RGCs. In preliminary studies we have shown that a particular pathway, called the stress induced response, is activated in animal models of glaucoma. We propose to study this pathway in more detail, and determine if inhibition of the stress induced response can reduce or prevent the loss of RGCs. If successful, this work could help provide the basis for the development of new strategies for the diagnosis and treatment of glaucoma.

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FUNDING PERIOD: APRIL 1, 2006 – MARCH 31, 2007

Stuart Foster, Ph.D.
Sunnybrook and Women’s College Health Sciences Center
Toronto, Ontario, Canada
Project: Imaging Ocular Anatomy and Blood Flow in Mouse Glaucoma
$43,530

Glaucoma involves retinal ganglion cell death and progressive optic nerve damage associated with loss of visual function. High frequency ultrasound imaging allows longitudinal assessment of diseases using anatomical information obtained via B mode imaging and functional information such as blood flow velocity via Doppler imaging. Methodologies and tools have been developed for the analysis of glaucoma phenotypes in mouse eyes, including the role of blood vessels in the glaucoma disease process. This project will use ultrasound microimaging and micro computed tomography (microCT) to contribute to the goals of further understanding glaucoma disease processes. Dr. Foster will measure anatomical parameters such as anterior segment angle, and measure functional parameters such as blood flow in the DBA/2J mouse model of glaucoma through disease progression. He will utilize the characterization of the progressive glaucoma disease process to determine the role of proteins which regulate the stability of blood vessels in the glaucoma disease process. He will also utilize antibody staining to characterize which proteins are important for blood vessel stability in eyes with glaucoma as the disease progresses. By investigating eye anatomy and blood flow we may be able to determine the role of the ocular blood vessels in the glaucoma disease process.

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FUNDING PERIOD: APRIL 1, 2006 – MARCH 31, 2008

Milam Brantley, Jr., M.D., Ph.D.
Washington University
St. Louis, MI
Project: Nmnat1 as a Neuroprotective Agent in Murine Glaucoma
$90,000

Glaucoma is the second leading cause of blindness worldwide and is characterized by degeneration of retinal ganglion cells (RGCs), whose axons make up the optic nerve.  It is generally accepted that degeneration of the RGC axons precedes programmed death of the cell bodies themselves.  Recent tissue culture experiments have shown that increased expression of the Nmnat1 gene can slow the rate of axonal degeneration in the face of axonal injury.  The purpose of this study is to evaluate the ability of overexpression of Nmnat1 to slow axonal degeneration in two mouse models of optic neuropathy.  In the first model, a short period of very high eye pressure will be used to cause RGC damage over 1-2 weeks.  The second model uses application of laser to the eye to moderately and stably raise eye pressure, closely simulating glaucoma.  A virus vector containing the Nmnat1 gene will be injected into eyes from each of these models, and the RGCs will be evaluated both morphologically and functionally to determine if Nmnat1 can protect the RGCs against damage.  This study will efficiently assess the potential of Nmnat1 to serve as an effective anti-glaucoma agent.

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Jeffrey Gidday, BS, Ph.D.
Washington University
St. Louis, MO
Project: Hypoxic Preconditioning and RGC Protection in Mouse Glaucoma
$90,000
Cells, tissues, organs, and species respond to stress by adaptations that render them more resistant to that same stress. Scientists are now capitalizing on this fundamental response, learning how cells defend themselves when presented with a mild stress, so as to better design therapeutics for true disease. Recently, it was learned that stressing the retina by having mice breath air with a low oxygen content (hypoxia) significantly reduces the death of ganglion cells in the retina when the mice develop experimental glaucoma. These findings imply that genes endogenous to these cells might be activated for glaucoma protection. The present study will focus on heme oxygenase-1, a protein believed to be responsible for the protection of hypoxia-stressed retinal ganglion cells in glaucoma. Dr. Gidday will make extensive determinations of how retinal hypoxia changes the expression of this protein, and will study mice missing or overexpressing this gene to confirm its participation in the protection. Heme oxygenase-1 therapy might represent a new treatment strategy for patients with glaucoma.

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Daniel Goldman, Ph.D.
University of Michigan
Ann Arbor, MI
Project: SOCS3 and Optic Nerve Regeneration in Zebrafish
$90,000

Glaucoma often leads to blindness due to optic nerve damage and retinal ganglion cell death.  Optic nerve regeneration may restore vision in patients suffering from glaucoma.  Unfortunately the damaged mammalian optic nerve does not readily regenerate.  Interestingly, fish regenerate their optic nerve following damage and therefore provide an ideal system for studying the mechanisms underlying successful optic nerve regeneration.  In a recent screen for genes that might mediate successful optic nerve regeneration in zebrafish, Dr. Goldman has identified suppressor of cytokine signaling 3 (SOCS3), which is highly induced in retinal ganglion cells that are regenerating their optic axons.  SOCS3 is a multifunctional SOCS protein that not only modulates the immune response, but can also influence a number of signal transduction cascades that impact cell survival and axon outgrowth. In this grant application he proposes to test whether SOCS3 is essential for successful optic nerve regeneration.  This will be accomplished by knocking down the expression of SOCS3 in adult retinal ganglion cells whose optic axons have been lesioned and assaying cell survival and optic axon regeneration in vivo.

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Pedro Gonzalez, Ph.D.
Duke University
Durham, NC
Project: Mesenchymal Stem Cells: A Therapeutic Approach to POAG
$90,000

Glaucomas are a group of eye diseases that lead to a gradual loss of vision that may result in blindness. There is still no cure for glaucoma, and current treatments consist of methods aimed at restoring the intraocular pressure levels. Argon laser trabeculoplasty has provided an effective therapy for glaucoma. However, the efficiency of laser therapy is limited to a short period of time, and repetitive procedures are usually required. One possible explanation for this limited efficiency is aging. As we get old, the regenerative potential of the tissues is diminished due to the lost and aging of progenitor cells. Results from the laboratory suggest an accumulation of aged cells in the drainage canal of the glaucomatous eye. The accumulation of aged nonfunctional cells may be responsible the limited regenerative potential following laser therapy. Dr. Gonazalez’s hypothesis is that transplantation of young progenitor cells following laser therapy will replace the laser-damaged cells; that these transplanted progenitor cells will repopulate the aged-drainage canal; and that this repopulation will recover the drainage canal functionality. He proposes to explore the use of adult mesenchymal stem cells from the bone marrow as a potential cellular replacement therapeutic strategy combined with laser therapy.

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Meredith Gregory, Ph.D.
Schepens Eye Research Institute
Boston, MA
Project: Membrane FasL as a Trigger for Pigmentary Glaucoma
$90,000

Pigmentary glaucoma is one of the most common forms of secondary glaucoma.  However, the underlying cause remains unclear.  The DBA/2J mouse is an animal model of pigmentary glaucoma and provides us with a unique tool to study the causes of pigmentary glaucoma in order to design improved and targeted treatments. Pigmentary glaucoma in DBA/2J mice is caused when the iris starts to breakdown, releasing particles of “pigment”. Cells of the immune system are activated to clear these pigment particles, causing severe inflammation and blockage of the eyes fluid outflow pathway.  Two gene defects are known to cause the release of pigmented particles, resulting in glaucoma.  However, there are other unknown factors that contribute to pigmentary glaucoma.  This research project will identify one of these previously unknown factors.  A unique form of a protein that is expressed in the eye only when pigmentary glaucoma develops has been identified.  This protein stimulates inflammation and destroys the fluid outflow system.  Completion of this project will identify a new and novel target for treating pigmentary glaucoma.  

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Richard Lee, M.D., Ph.D.
Bascom Palmer Eye Institute
Miami, FL
Project: Proteomic Characterization of Pseudoexfoliation Glaucoma
$90,000

Pseudoexfoliation glaucoma (PEX) is the most common form of open angle glaucoma with an identifiable cause. Pseudoexfoliation glaucoma is defined by the presence of pseudoexfoliation “material” in the anterior segment of the glaucomatous eye, typically layered on the lens capsule in a bull’s eye configuration.  This project will 1) identify the PEX proteins using advanced proteomic approaches and 2) characterize the components of the PEX protein complex using molecular techniques. Preliminary experiments have identified proteins associated with the pathophysiology of PEX glaucoma, but not the causative PEX material proteins themselves. Using differential protein expression analysis, Dr. Lee will identify the PEX material proteins present on PEX patient lens capsules. Antibodies to these PEX proteins will be used to discover the other members of the PEX material complex and understand how PEX material proteins molecularly assemble in the anterior segment of the eye to cause glaucoma.  Identification of PEX-specific proteins and determination of the components of PEX material will provide insight into the pathogenesis of pseudoexfoliation glaucoma. A better understanding of the molecular basis of PEX glaucoma will lead to the development of novel molecularly targeted, non-intraocular pressure dependent therapies that may prevent the formation of PEX material.

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Jeffrey Marchant, Ph.D.
Tufts University School of Medicine
Boston, MA
Project: Matrix Interactions Pertinent to High IOP and Glaucoma
$90,000

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and results from alteration of the pathway that drains aqueous humor from the anterior eye. While studies have been performed to characterize this pathway in human and non-human primate tissues, the understanding of its organization is still very limited. The outflow pathway is comprised, in part, of a region known as the trabecular meshwork (TM). The TM is a series of cells and connective tissues organized as a filter. Alterations in several TM components have been correlated with elevated IOP. Dr. Marchant has identified a new component in the TM that he hypothesizes will stabilize this region and help to regulate normal IOP. Dr. Marchant will examine the TM in the mouse to evaluate the organization of this and other components thought to regulate IOP. He will then exploit the genetic capabilities of the mouse and examine mutants that have altered expression of key TM regulatory components, as well as evaluate the affect these alterations have on TM function and IOP regulation. Given the similarities between the components in mouse and human TM tissues, these findings will likely be highly relevant to human IOP regulation and thus may lead to intervention strategies for the future.

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Hiroshi Nakamura, M.D., Ph.D.
University of Illinois at Chicago
Chicago, IL
Project: Supression of Ocular Scarring by RNA Interference
$90,000

Connective tissue growth factor (CTGF) is an important mediator of wound healing in various tissues. In the eye, CTGF has been implicated in corneal wound healing, and subconjunctival scarring following glaucoma surgery. This project proposes to employ RNA interference (RNAi) technology to target CTGF. It is hoped that silencing of the growth factor will help block the scarring action. The efficacy and consequence of the siRNAs will be studied in cultured conjunctival fibroblasts. Investigation in an ocular inflammation/fibrosis model in mouse will be followed to determine whether downregulation of CTGF would reduce inflammation and scarring. The current proposal is highly significant for its clinical impact since excessive scarring is often a major cause of impaired vision and blindness. Results obtained from this application may lead to novel therapeutic modalities to prevent inflammation and scarring after glaucoma surgery and in eye diseases including corneal opacities.

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Michael Nork, BS, MS, M.D.
University of Wisconsin-Madison
Madison, WI
Project: The Significance of Outer Retinal Injury in Glaucoma
$89,562

Chronic glaucoma results in the loss of retinal ganglion cells.  Much of basic glaucoma research has, appropriately, focused on these cells and their axonal connections as they pass through the optic nerve.  However, previous work by the principal investigator and by other laboratories have now established that the outer retina (specifically, the photoreceptors) is also affected in both human chronic glaucoma and in a non-human primate model of chronic glaucoma.  The significance of this finding is unknown.  Dr. Nork plans to apply new research methodologies for examining the relationship between the blood supply to the outer retina and the retinal pathology found in glaucoma.Blindness in glaucoma is caused by retinal ganglion cell loss.  Direct injury (either mechanical or vascular) to the optic nerve most likely represents a significant effect.  Even so, outer retinal ischemia may play a contributory role in RGC death.  With this research into the regional effects of retinal damage in animal models of glaucoma, Dr. Nork hopes to test if outer and inner retinal injury in glaucoma are related.  If these and other studies show this to be the case, it could lead to new pathways for pharmacologic intervention in this often inadequately controlled disease process.

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Deborah Otteson, B.Sc., Ph.D.
University of Houston
Houston, TX
Project: Regulation of EphA Expression in Retinal Ganglion Cells
$85,000

In the visual system, signaling between Eph/ephrin proteins plays key role in axon path-finding in the optic nerve, determining which retinal ganglion cell (RGC) axons will cross at the optic chaism and regulating the initial positioning of RGC synapses in the brain. Gene expression is largely regulated by factors that bind to regulatory regions called promoters located in the DNA and this project’s hypothesis that the spatial and cellular expression patterns of Eph receptor genes in RGCs are regulated by specific transcriptional regulatory factors. These studies seek to understand the molecular and cellular mechanisms that regulate expression in RGCs by identifying the promoters of the EyhA genes, determining the binding sites for retinal proteins and testing a group of specific transcription factors for their ability to activate the EphA promoters in cultured retinal cells. The long term goals are to identify the network of regulatory mechanisms controlling gene expression in RGCs. This will contribute to our basic knowledge of RGC biology and may identify novel targets for developing new therapeutic agents and will enhance the future development of gene- and cell-based strategies for repair and regeneration of injured RGC axons to restore lost vision in patients with glaucoma.

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Darryl Overby, Ph.D.
Tulane University
New Orleans, LA
Project: How Does Segmental Outflow Affect Outflow Resistance?
$90,000

Glaucoma is a disease typically associated with elevated intraocular pressure (IOP) caused by increased resistance to aqueous humor outflow. Glaucoma is treated clinically by reducing IOP, but the precise factors responsible for controlling IOP and outflow resistance are not well understood. To improve the understanding of outflow resistance, Dr. Overby proposes to study how the hydrodynamic patterns of aqueous humor outflow change in response to stimuli that affect outflow resistance. His hypothesis is because aqueous humor is confined to flow through only a fraction of total area of outflow pathway, outflow resistance is correlated to the area that is actively involved in hydrodynamic filtration of aqueous humor. To test this hypothesis, he will aim to develop a new tracer method that will combine with confocal microscopy to visualize the hydrodynamic patterns of outflow and measure the active area of aqueous humor filtration in human eyes. The second aim is to use this tracer technique to quantify the relationship between outflow resistance and filtration area for changing IOP that causes a change in outflow resistance. The long-term goal of this project is to translate this fundamental understanding of outflow hydrodynamics into a strategy to reduce outflow resistance and IOP in glaucomatous eyes.

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Hemant Pawar, Ph.D.
University of Michigan
Ann Arbor, MI
Project: Genetic Risk Factors and Glaucoma Outcomes
$90,000

Mutations that alter the myocilin (MYOC) gene product are known to cause glaucoma, but it has also been suggested that glaucoma severity might be affected by mutations in the regulatory promoter region that affects level of expression of the gene. Because there are contradictory reports regarding the role of variants in this MYOC regulatory region, it is important to carry out an optimal study aimed at evaluating whether MYOC regulatory variants can affect glaucoma severity or outcomes. Dr. Pawar proposes to use the Collaborative Initial Glaucoma Treatment Study (CIGTS) and Advanced Glaucoma Intervention Study (AGIS) study samples for analyzing this risk factor in the MYOC gene. This sample set offers well-documented clinical information and will help establish whether there is a correlation between the MYOC genotypes and the outcomes of the glaucoma clinical trial samples. In fact, this project may help physicians predict things about severity and outcome for their patients, and assist them in using this information in designing an optimal treatment plan. One of the important features of the proposed work is that it will provide important information whether or not the sequence variant turns out to be predictive of outcome.

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Daniel Ts’o, Ph.D.
SUNY Upstate Medical University
Syracuse, NY
Project: Non-invasive Retinal Functional Imaging of Animal Models
$90,000

Neural tissue such as the brain or the retina of the eye exhibits a visible vascular response (an optical signal) when it is active, and sensitive cameras can be used to record these signals.  This lab has recently adapted this technique to the non-invasive monitoring of retinal function. The promise of Dr. Ts’o project is the development of a reliable, objective instrument for monitoring the activity of the retina, in health and disease, simply by taking pictures of its response to patterns of light. Glaucoma is one disease that may greatly benefit from such an instrument. It would facilitate the early detection and characterization of glaucoma in patients and help in the monitoring of the progress of the disease and its treatment. This project aims to target this new technique specifically to the monitoring of the health and activity of the ganglion cells of the retina, the cells that are most affected by glaucoma. Dr. Ts’o then proposes to directly test how well this technique reveals glaucoma and its progression.  These developments are designed to make this new technology most useful for the diagnosis and treatment of glaucoma.

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Derek van der Kooy, Ph.D.
University of Toronto
Toronto, Ontario, Canada
Project: Retinal Stem Cells for Transplant in a Glaucoma Model
$90,000

In patients with glaucoma, vision is lost because of the death of nerve cells in the eye called retinal ganglion cells.  Although treatments exist for glaucoma, many patients still lose vision because of the continued loss of retinal ganglion cells.  It is well recognized that stem cells offer hope for the treatment of many diseases.  Dr. van der Kooy’s laboratory was the first to describe the isolation of retinal stem cells from adult human and adult mouse eyes.  When these stem cells are transplanted into mice, they have the remarkable capacity to integrate into the host retina.  Furthermore, retinal stem cells can form all the major cell types that are found in the retina, including retinal ganglion cells.  Dr. van der Kooy plans to transplant adult mouse retinal stem cells into the eyes of mice that have glaucoma and see whether these cells can replace lost retinal ganglion cells.  This research will lead towards a day when it will be possible to take just a few retinal stem cells from a patient’s eye, expand their numbers in the lab, and then return them to that same patient in order to treat glaucoma. 

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FUNDING PERIOD: APRIL 1, 2005 – MARCH 31, 2007

Raymond Chuen-Chung Chang, Ph.D.
The University of Hong Kong
Hong Kong, China
Project: Microglia/Microphages and Neuroprotection in Glaucoma

Glaucoma is a chronic disease in which the neurons, called retinal ganglion cells, undergo degeneration. Another trait of developing glaucoma is an increase of pressure within the eyes. Recently, a novel approach was proposed to utilize our body immunity to protect neurons in the eyes. Dr. Chang’s study aims to define which factors or what conditions for the activation of innate immune cells can lead these cells to elicit protective effects. He will also study how a Chinese medicine, Chinese Wolfberry, exhibits protective effects to neurons in the eyes via mild activation of innate immune cells. Knowledge of how body immunity exerts protective effects to neurons in the eyes will hopefully pave a new road for therapeutic intervention against loss of vision in glaucoma.

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Deepak Edward, M.D.
University of Illinois at Chicago
Chicago, IL
Project: In Vivo Study of Femtosecond Laser Ablation

The current procedure for reducing eye pressure is to make an opening in the trabecular meshwork to allow the aqueous humor to flow more freely into the Schlemm’s canal. A common form of this procedure is known as laser trabecular ablation, or LTA. This procedure involves long pulse durations that can cause collateral damage, including inflammation and scarring, and eventually leads to closure of the incision. Dr. Edward plans to study the results of a new technique using an ultrafast Titanium Sapphire laser, which has been found to overcome all of the aforementioned problems. By studying changes in the treated eye over a period of up to two months, Dr. Edward hopes to better understand the interplay between mechanical effects of the laser and the biologic response that might occur during wound healing.

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Dorette Ellis, Ph.D.
University of Florida
Gainesville, FL
Project: The Role of sGC Activators as Ocular Hypotensive Agents

Researchers have shown that topical application of nitric oxide to rabbit and monkey eyes causes significant decreases in intraocular pressure. This would suggest that nitric oxide could be used to treat high intraocular pressure in glaucoma. However, higher doses of nitric oxide are less effective than lower doses and constant use of some nitric oxide donors result in tolerance. Nitric oxide binds to its target enzyme called soluble guanylate cyclase causing the formation of cGMP, and subsequent activation of other proteins and effects. There are gaps in our knowledge about the involvement of nitric oxide and soluble guanylate cyclase, and the role of nitric oxide in glaucoma. A better understanding of the interaction between soluble guanylate cyclase activators, their target enzyme, and down stream effectors will lead to new strategies in the treatment of glaucoma.

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Haiyan Gong, M.D., Ph.D.
Boston University School of Medicine
Boston, MA
Project: Can Wash-Out be Induced in the Human Eye to Reduce IOP?

In order to be transparent so that vision is possible, some of the tissues of the eye have no blood supply. These tissues depend upon a clear nutritive fluid called aqueous humor in order to survive. Used aqueous humor leaves the eye through a specially designed filtration tissue known as the trabecular meshwork. The finest mesh of this filer is called the juxtacanalicular region (JCT). After flowing through the JCT, used aqueous humor passes through the inner wall lining cells of Schlemm’s canal and into the veins leaving the eye. Disruption of connectivity between the inner wall of Schlemm’s canal and the JCT is predicted to increase aqueous humor outflow facility and may lead to the development of novel therapeutic agents for the treatment of the elevated pressure associated with glaucoma.

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Cynthia L. Grosskreutz, M.D., Ph.D.
Massachusetts Eye and Ear Infirmary
Boston, MA
Project: Heat Shock Proteins in Experimental Glaucoma

Heat shock proteins (HSP) are a group of highly conserved proteins that act in a coordinated response to environmental and physiological stress. It has been recently observed that one member of this protein family, HSP27, is elevated in certain genetic models of glaucoma. Dr. Grosskreutz hopes to discover whether experimentally increasing HSP27 levels in the eye will prevent neuronal death in the retina in glaucoma. She will apply this gene therapy to increase and decrease HSP27 levels in the retina and record changes. Together, these results will provide important new information regarding the role of heat shock proteins in retinal ganglion cell death in glaucoma, and provide clues to new neuroprotective treatment approaches for this blinding disease.

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Paul Kaufman, M.D.
University of Wisconsin Medical School
Madison, WI
Project: A.G.E. Crosslink Breakers for Ocular Disorders

Dr. Kaufman will determine whether the crosslink breaker compound, alagebrium, can alter intraocular pressure, improve the ease with which fluid passes out of the eye (outflow facility) via the conventional outflow pathways, and improve the ability to focus in response to a pharmacologic stimulus. Completion of these studies will clarify whether crosslink breaker compounds have any promise for further development as therapies for primary open angle glaucoma or presbyopia, the age-related loss of focal ability. This type of therapy would target a different pathway than all other glaucoma therapeutics and create the first pharmacologic therapy for presbyopia.

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David Mackey, M.D.
Royal Victorian Eye & Ear Hospital
East Melbourne, Australia
Project: Ophthalmic Examination of Dizygotic Twins in Queensland

Glaucoma is thought to have a major genetic component. Several genes have been identified, but so far these only accounts for 5% of glaucoma cases. Twin studies are an important tool for determining the relative contribution of genes or environment in any measure. If there is very little genetic component, then identical twins will vary as much as non identical twins. Dr. Mackey will analyze pressure, refraction, optic nerve, corneal thickness and many other measures in his study, and then compare all the numerical measurements of the twins with their DNA markers to discover where similar twins consistently have similar DNA markers. Discovering the genes that cause glaucoma will enable other family members to be tested and predict who is at high risk or low risk of developing glaucoma. This will allow better early screening for glaucoma and potentially lead to the development of new treatments.

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Catherine McCarty, Ph.D., M.P.H.
Marshfield Clinic Research Foundation
Marshfield, WI
Project: A Population-Based Study of Pharmacogenetics and Glaucoma

Beta-blockers are a common class of medication used to lower intraocular pressure. Interestingly, this same class of medications is used orally to treat high blood pressure, and genetics have been shown to play a role in how a person responds to this medication. Dr. McCarty believes that genetics is also associated with how a person responds to a prescription for medication to lower intraocular pressure. Her goal is to ultimately improve treatment of patients with glaucoma and ocular hypertension. In the future this study may lead to an assessment as to whether prescription medications based on genotype would improve cost effectiveness and preserve visual function in people with glaucoma and intraocular hypertension.

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