PREVENTION OF RETINAL LIGHT DAMAGE BY ZINC OXIDE COMBINED WITH ROSEMARY EXTRACT: ▼
Zinc oxide effectively reduces visual cell loss in rats exposed to intense visible light and is known to slow the rate of disease progression in advanced stages of age-related macular degeneration. The goal of this study was to determine the efficacy of zinc oxide in combination with novel and well-established antioxidants in an animal model of light-induced oxidative retinal damage.
One group of male Sprague-Dawley rats was pretreated with zinc oxide with or without a detergent extract of rosemary powder and then exposed to intense visible light for 4-24 hours. Another group of animals received zinc oxide combined with rosemary oil diluted with a mixture of polyunsaturated fatty acids and a third group was given an antioxidant mineral mix containing zinc oxide, as recommended by the Age Related Eye Disease Study group’s first clinical trial (AREDS1).
It was found that in the rat model of acute retinal light damage, zinc oxide combined with a detergent extract of rosemary powder or rosemary oil is more effective than treatment with either component alone and significantly more effective than an AREDS mixture containing a comparable dose of zinc oxide. Light-induced oxidative stress in animal models of retinal degeneration can be a useful preclinical paradigm for screening novel antioxidants and for testing potential therapeutics designed to slow the progression of age-related ocular disease.
To access this article: www.molvis.org/molvis/v19/1433/
In the second year of the funding, October 2013 – September 2014, we found that long term environmental light intensity is a major effector of photoreceptor cell survival, following acute photo-oxidative stress, and of retinal protein and gene expression. Higher levels of light in the environment lead to the loss of opsin from cone cells, with modest effects on the cone cell protein called arrestin (mCAR). This may result from a shortening of the opsin containing cone outer segments, without loss of the entire cone photoreceptor. Acute intense light exposure also leads to the loss of rod and cone cell opsins and arrestins, but unlike long term environmental light, the loss of visual cells in this case is largely irreversible. Antioxidants can prevent photoreceptor cell death and the more effective an antioxidant is, the greater the rate of visual cell survival. In the original AREDS study zinc oxide accounted for about 70% of the benefit, thus we sought to enhance the less effective antioxidant fraction of the AREDS formulation. Toward this goal, we fed AREDS, or AREDS plus rosemary to rats daily for six weeks and then treated them with intense white light. In this study the protective efficacy of AREDS against photo-oxidative visual cell damage was enhanced by rosemary supplementation as well as by the major rosemary component carnosic acid. Chronic administration of rosemary, or of its individual antioxidants, may be a useful adjunct to the therapeutic benefit of AREDS in slowing the loss of photoreceptor cells and the progression of AMD to advanced disease.
Molecular Vision, “Prevention of retinal light damage by zinc oxide combined with rosemary extract,” Daniel T. Organisciak, R. M. Darrow, C.M. Rapp, J.P. Smuts, D. W. Armstrong, J.C. Lang. (June 2013, v19,1433-1445) This study was conducted with IRRF support – Dr. Daniel Organisciak.
Photo left: Dr. Daniel T. Organisciak
SYNTHESIS AND MECHANISTIC STUDIES OF A NOVEL HOMOISOFLAVANONE INHIBITOR OF ENDOTHELIAL CELL GROWTH: ▼
Plos One, “Synthesis and Mechanistic Studies of a Novel Homoisoflavanone Inhibitor of Endothelial Cell Growth,” Halesha D. Basavarajappa, Bit Lee, Xiang Fei, Daesung Lim, Breedge Callaghan, Julie A. Mund, Jamie Case, Gangaraju Rajashekhar, Seung-Young Seo, Timothy W. Corson, Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana. (April 2014, vol. 9, Issue 4) This study was conducted with IRRF support – Timothy W. Corson.
Preventing pathological ocular angiogenesis is key to treating retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. At present there is no small molecule drug on the market to target this process and hence there is a pressing need for developing novel small molecules that can replace or complement the present surgical and biologic therapies for these neovascular eye diseases. Previously, an antiangiogenic homoisoflavanone was isolated from the bulb of a medicinal orchid, Cremastra appendiculata. In this study, the team presented the synthesis of a novel homoisoflavanone isomer of this compound. The compound, SH-11052, has antiproliferative activity against human umbilical vein endothelial cells, and also against more ocular disease-relevant human retinal microvascular endothelial cells (HRECs). Tube formation and cell cycle progression of HRECs were inhibited by SH-11052, but the compound did not induce apoptosis at effective concentrations. SH-11052 also decreased TNF-α induced p38 MAPK phosphorylation in these cells. Intriguingly, SH-11052 blocked TNF-α induced lκB-α degradation, and therefore decreased NF-κB nuclear translocation. It decreased the expression of NF-κB target genes and the pro-angiogenic or pro-inflammatory markers VCAM-1, CCL2, IL8, and PTGS2. In addition SH-11052 inhibited VEGH induced activation of Akt but not VEGF receptor autophosphorylation. Based on these results it is proposed that SH-11052 inhibits inflammation induced angiogenesis by blocking both TNF-α and VEGF mediated pathways, two major pathways involved in pathological angiogenesis. Synthesis of this novel homoisoflavanone opens the door to structure-activity relationship studies of this class of compound and further evaluation of its mechanism and potential to complement existing antiangiogenic drugs.
Corson Lab Group. Timothy Corson in foreground.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, “THE ROLE OF THROMBIN IN PROLIFERATIVE VITREORETINOPATHY”: ▼
Investigative Ophthalmology & Visual Science, “The Role of Thrombin in Proliferative Vitreoretinopathy,” Jeroen Bastiaans, Jan C. van Meurs, Verena C. Mulder, Nicole M.A. Nagtzaam, Marja Smits-te-Nijenhuis, Diana C. M. Dufour-van den Goorbergh, P. Martin van Hagan, Herbert Hooijkaas, and Willem A. Dik, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. (July 2014, vol. 55, No. 7) This study was conducted with IRRF support – Willem A. Dik.
Proliferative vitreoretinopathy (PVR) is an inflammatory fibrotic disorder that can develop after rhegmatogenous retinal detachment, and is the most common failure of retinal detachment repair. Proliferative vitreoretinopathy development is characterized by the formation of subretinal, intraretinal, and/or epiretinal fibroproliferative membranes that cause the retina to detach due to the contractile properties of myofibroblasts that are abundantly present in these membranes. Retinal pigment epithelial (RPE) cells contribute to the formation of these fibroproliferative membranes through the secretion of cytokines and growth factors, proliferation, and dedifferentiation into extracellular matrix-producing myofibroblasts.
Current knowledge of the underlying pathobiological processes in PVR is still limited. Vitreous of patients with established proliferative vitreoretinopathy contains elevated levels of thrombin, which induces the production of proliferative vitreoretinopathy-associated cytokines, and growth factors by RPE. The purpose of this study is to determine the role of thrombin in the development of proliferative vitreoretinopathy (PVR).
Dr. Dik’s research group: Sita Virakul, Willem Dik, Jeroen Bastiaans, Nicole Nagtzaam, Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
THE RESTORATION PROCESS HAS BEGUN FOR COMPLEX VISION: ▼
DAY ONE: A flurry of activity surrounded the Callahan Eye Hospital during April 7-12, 2014, when the first phase of the restoration process was begun for Complex Vision. A sense of community was enjoyed as a couple of locally owned and operated Birmingham businesses came together to perform the preliminary services before the panels of the 30-foot aluminum sculpture could be removed. Many of the workmen remembered when the sculpture was erected in 1976, and soon began relating their own impressions of that event. “We had never seen anything like it, but knew something very important was happening,” said one, and “My Dad would drive up and down University Boulevard and we kids would watch as the sculpture changed,” remarked another. Although the memories were individual, all expressed their excitement over being a part of this monumental undertaking.
DAY TWO: Once the insects were eradicated, the unpleasant job of removing almost four decades of accumulated waste matter had to be performed. Although this crew did not have to deal with poisonous spiders, as the brown recluse, they were exposed to potentially toxic fumes.
DAYS THREE, FOUR AND FIVE: After the structure and areas around it were cleared, it was safe to begin the dismantling process of Complex Vision. Dennis Carhart, Art Creations & Restorations (below left), and his crew arrived and began taking down the panels. The area was patrolled by a security guard at all times during the process.
After a week of intense work, the panels had been removed and were packed in individual crates for transport to Art Creations & Restoration in West Palm Beach, Florida, where they will be stripped and prepared for a new finish. All of the panels were removed in three days, however, it is expected that up to three weeks will be needed to reattach them after being restored. The restoration process will take approximately 6 months to complete with plans for a re-dedication ceremony set for the fall of 2014.
Thanks to everyone who helped with this phase of the restoration of Complex Vision!!
At the end of the day, the pest control crew was all smiles and glad to have the job behind them…but still expressing their happiness at being part of the project!
After several hours of fighting the wind, the tarp was finally in place so that the back space could be treated for poisonous insects.
Another day of hard work brought the project further along and all was ready for the panels to begin coming down.
IRRF Executive Director, Sandra Blackwood with security guard, Jon David Franklin
THE RESTORATION OF COMPLEX VISION CONTINUES: ▼
The restoration process continues for Complex Vision, the 30 by 30 foot sculpture by renowned Israeli sculptor Yaacov Agam. After gracing the front of the Callahan Eye Hospital for the last 38 years, the art was dismantled piece by piece in April 2014, each panel packaged individually and then transported to Art Creations and Restorations in West Palm Beach, Florida.
Many steps must be completed before the actual process of applying the colors can begin. The panels are laid out in order and a blueprint is made to document the corresponding paint colors for each panel. Only until all the colors, shapes and positions are documented can paint be removed. Any imperfections in the exposed metal must be repaired and then buffed smooth. All panels are acid washed before they can be etched primed and then filler primed. Most of this has been accomplished and sample colors have been sent to Mr. Agam in Paris, who is scheduled to come to West Palm Beach to personally approve all colors before they can be transferred to the panels.
Dennis Carhart, owner of Art Creations and Restorations, has been working with Yaacov Agam since 1993. The two met when Agam rented Carhart’s spacious workshop to use for a restoration project, and after observing the attention to color, measurement and detail that Carhart incorporated in his work, their relationship flourished. Carhart has assisted with many of Agam’s restoration projects worldwide over the past 20 years.
In addition to Dennis Carhart, several other craftsmen have been brought to the United States to help with the project. One of these is Andy Krocin, who traveled from Peru to add his many years of experience to the project.
Dennis Carhart, owner of Art Creations & Restorations and Andy Krocin, explain to Sandra Blackwood, IRRF, the process of stripping the panels and preparing them for the etching and filler primer process.
Dennis Carhart points out how badly some of the colors
had faded, making them difficult to match.
Andy Krocin, sands a panel to remove the faded colors, and after all imperfect-
ions have been buffed smooth, applies an acid wash to remove any residue.
Once this process is finished, the panel can be etched primed and filler primed.
EYE SITE OFFERS NEW INSIGHT ON AGE-RELATED MACULAR DEGENERATION: ▼
With seed money from philanthropic foundations, and a subsequent grant from the National Eye Institute, Curcio started Project MACULA. Her team catalogued 142 donor eyes: 82 with AMD and 60 controls. Each was tagged with critical information — such as exact measurements of the thickness of each tissue layer, along with a glossary and references — and both laboratory and OCT images. The site officially launched in 2013.
In the process of systematically reviewing the histology, Curcio’s team made major discoveries about the pathology of AMD — including a natural history of the principal lesions associated with the disease, known as drusen; the first major description of a new, drusen-like lesion, and the first comprehensive description of the neurodegeneration of AMD involving photoreceptors and the retinal pigment epithelium, which supports the photoreceptors. These findings have led to numerous peer-reviewed journal articles and invitations to major clinical meetings. “Leading ophthalmologists want this information to develop guidelines for trials,” for example, Curcio explains. “This is putting the right tools into the hands of the right workforce.”
“Having the histologic images available has helped me in interpretations and integration of multimodal imaging in the clinic,” agreed Richard Spaide, M.D., a renowned specialist in the diagnosis and treatment of retinal diseases who practices at Vitreous-Retina-Macula Consultants of New York. He has collaborated with Curcio on Project MACULA since 2009, co-authoring several well-cited papers that link clinical presentation on OCT with anatomical features seen in histologic images. “As with anything in science, there is plenty we don’t know," Spaide said. "So when a subtle finding is recognized in an imaging modality in the clinic, it is helpful to go back to the known histology to put the new finding into some kind of perspective.”
Project MACULA has also had the desired effect of fostering important collaborations to advance knowledge about AMD, with the ultimate goal of developing new treatments and cures, Curcio said.
For example, Curcio and collaborator Dwight Stambolian, M.D., Ph.D., associate professor of ophthalmology and genetics at the University of Pennsylvania, recently submitted a funding request to add genetics to the equation. They propose obtaining a new set of donor eyes and uploading one eye from each pair to Project MACULA and sending the other to Stambolian’s team for comprehensive and robotic sequencing of RNA. Since AMD is a bilateral disease, affecting both eyes, this would create links in understanding of AMD from genetic variation to cells to clinical presentation.
“Connecting changes on the cellular level with changes in gene expression will hopefully allow us to develop new targets for new drug therapies,” said Curcio. “Since Project MACULA also links those changes with clinical images, it will also show physicians how these changes are presenting in the patient so they know when to start treatment, or in some cases, what does not need to be treated.” This information advances the goal of personalized medicine for individual patients, Curcio adds.
TISSUE, TECHNOLOGY AND OTHER SUPPORT
The project would not have been possible without several key partners, Curcio points out. “High-quality tissue made discoveries possible at Project MACULA,” she said. “Very few people are blessed with a resource like the Alabama Eye Bank, a highly productive eye bank that is able to obtain lots of tissue rapidly and thus meet our research needs.” Another invaluable contributor was the UAB Department of Computer and Information Sciences. Associate Professor Kenneth R. Sloan, Ph.D., his students and CIS staff provided the expertise and resources to create and host the Project MACULA site, Curcio notes.
The project also owes much to private funding partners such as the Birmingham-based International Retinal Research Foundation (IRRF), Curcio adds. Initial awards from the IRRF and the Edward N. & Della L. Thome Memorial Foundation allowed Curcio to purchase a large number of donor eyes from the Alabama Eye Bank, which formed the nucleus of Project MACULA. Another IRRF award supported the collection of pilot data that Curcio used to secure a large grant from the National Eye Institute, which funded Project MACULA’s creation.
“It isn’t possible to obtain large federal grants without first collecting pilot data,” said Curcio. “Without the funding support of IRRF during the early stages, Project MACULA would have never gotten off the ground.”
“We saw Project MACULA as an extraordinary opportunity to expand AMD histopathology in hopes of translation to better clinical interpretations of this degenerative disease,” said Sandra Blackwood, executive director of the IRRF. “This resource is serving as a valuable catalyst to both bench and clinical science.”
This article was originally published on the UAB MIX RESEARCH BLOG.
Research associate Jeffrey Messinger performing ex vivo color fundus photography of a donor eye with AMD. Project MACULA shows ex vivo color fundus photography in addition to OCT scans for each eye.
Users can reveal detailed annotations for each of the microscope and OCT images contained on the Project MACULA site.
CHRISTINE A. CURCIO, PhD IS AWARDED MATCHING FUNDS FOR THE LUDWIG VON SALLMANN PRIZE: ▼
Christine A. Curcio, PhD is Awarded Matching Funds for the Ludwig von Sallmann Prize:
The International Retinal Research Foundation (IRRF) provided funds to match the Ludwig von Sallman Prize awarded to Christine A. Curcio, PhD, University of Alabama at Birmingham, Department of Ophthalmology, at the 2014 International Society for Eye Research meeting in San Francisco. The von Sallman Prize carries a $50,000 cash award for the recipient and with the additional $50,000 from the IRRF, Dr. Curcio will invest in and accelerate the next phase of research on age-related macular degeneration, through technology development and staff/student training. Dr. Curcio
and her lab are focusing on histological and ultrastructural validation of clinical imaging technologies focused on the retinal pigment epithelium (RPE), a cell central to age-related macular degeneration. These include spectral domain and polarization sensitive optical coherence tomography and total and hyperspectral autofluorescence. With continued access to pathology specimens through the Alabama Eye Bank, Curcio will build the Project MACULA website into a global resource for RPE pathobiology. “This is especially fitting because the IRRF was an important contributor to the original eye repository and website development,” said Curcio recently.
Ludwig von Sallmann was a distinguished international ophthalmologist and ophthalmic investigator who served on the staff of Vienna, Peking and Columbia Universities and the Ophthalmology Branch of the former National Institute of Neurological Diseases and Blindness at the National Institutes of Health. His wife, Henrietta von Sallmann, established a trust fund to award, in his memory, a cash prize every two years to an individual who has distinguished himself/herself by making a significant contribution to vision research and ophthalmology.
The Ludwig von Sallmann Prize is one of four International Prizes that are awarded in even years at the Biennial Meeting of the International Society for Eye Research.
Dr. Curcio; and Sandra Blackwood, IRRF Executive Director
IMPROVED CELL METABOLISM PROLONGS PHOTORECEPTOR SURVIVAL ... ▼
EXPERIMENTAL EYE RESEARCH
June 22, 2016
Oncotarget, Improved cell metabolism prolongs photoreceptor survival upon retina-pigmented epithelium loss in the sodium iodate induced model of geographic atrophy, Marina Zieger and Claudio Punzo, Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical Center, Worcester, MA. This study was conducted with IRRF support.
Age-related macular degeneration (AMD) is characterized by malfunction and loss of retinal-pigmented epithelium (RPE) cells. Because the RPE transfers nutrients from the choriocapillaris to photoreceptor (PR), PRs are affected as well. Geographic atrophy (GA) is an advanced form of AMD characterized by severe vision impairment due to RPE loss over large areas. Currently, there is no treatment to delay the degeneration of nutrient deprived PRs once RPE cells die. Here we show that cell-autonomous activation of the key regulator of cell metabolism, the kinase mammalian target of rapamycin complex 1 (mTOR1), delays PR death in the sodium iodate induced model of RPE atrophy. Consistent with this finding loss of mTORC1 in cones accelerates cone death as cones fail to balance demand with supply. Interestingly, promoting rod survival does not promote cone survival in this model of RPE atrophy as both, rods and cones suffer from a sick and dying RPE. The findings suggest that activation of metabolic genes downstream of mTORC1 can serve as a strategy to prolong PR survival when RPE cells malfunction or die.
To read this paper in its entirety, please CLICK HERE.
To visit the Punzo Lab website, please CLICK HERE.
Improved cell metabolism prolongs photoreceptor survival upon retina-pigmented epithelium loss in the sodium iodate induced model of geographic atrophy
Left: Dr. Claudio Punzo (middle) and his staff. Marina Zieger is pictured far left.