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Jonathan H. Lass, M.D., Charles I Thomas Professor and Chairman

Eric Pearlman, Ph.D., Professor and Director of Research

OLERF funds have contributed significantly to an unprecedented year for the recently re-named Department of Ophthalmology and Visual Sciences by Case Western Reserve University and the constitution of the department as an Eye Institute at University Hospitals Case Medical Center. The Department has moved into two floors of renovated, consolidated laboratory, administrative and conference facilities in the historic Institute of Pathology on the CWRU Medical School campus. Faculty occupying this space include Drs. Eric Carlson, Ram Nagaraj, Eric Pearlman and Carlos Subauste. In the last year, we also recruited Drs.Tadeo Maeda, Paul Park, Irina Pikuleva and Johnny Tang who make up our retinal degeneration program. This recruitment effort, which was undertaken with support from OLERF funds, brings our research group to eight full time faculty in this space.

In addition, Dr. Jonathan Lass, Chair of the Department and Dr. Loretta Sczcotka-Flynn have clinical research programs that are partly supported by OLERF. This group, together with some fourteen other NEI funded vision investigators in ten other departments, comprise the faculty of the Case Visual Sciences Research Center (VSRC). The VSRC also has a NEI funded training grant and NEI funded Core Grant, with the newly renovated space in the Pathology Institute also including laboratories of most of the Core modules.

1) Ocular Immunology, Infection and Inflammation: Drs. Carlson, Pearlman, Subauste.

2) Aging and Diabetes: Drs. Nagaraj and Subauste.

3) Retinal degeneration: Drs. Maeda, Park, Pikuleva, and Tang

4) Molecular epidemiology of eye diseases: Drs. Lass and Szczotka-Flynn

Eric Carlson, Ph.D., Instructor: OLERF funds were used for technical support in Dr. Eric Carlson’s studies on the role of matrix protein in inflammation and corneal transparency. The results from Dr. Carlson’s projects have been published in the highly prestigious Journal of Biological Chemistry in 2007, and a second paper has been submitted. The studies on corneal transparency will determine the impact of various inflammatory stimuli on corneal transparency as regulated by the keratansulfate proteoglycans that comprise the corneal matrix. These OLERF supported studies were also used to apply for an NEI R01 grant which recently received a fundable score below the 10th percentile. Eric Pearlman, Ph.D., Professor: The OLERF departmental award continues to contribute to the projects in Dr. Pearlman’s laboratory, and this last year has helped launch a new initiative in fungal keratitis. Dr. Pearlman’s studies on ocular onchocerciasis (river blindness) have progressed considerably, with three original articles and three invited reviews. For our studies on innate immunity in the cornea (Toll Like Receptors), we published a study that not only increases our understanding of pathogen recognition molecules in the cornea, specifically in corneal epithelial cells, but also reveals a fundamental regulatory mechanism that has implications beyond ocular disease. However the main contribution of OLERF funds has been in the area of fungal keratitis. Two studies have been undertaken to examine the organism that was the cause of the 2005 – 2006 outbreak of contact lens associated Fusarium keratitis in the USA. One manuscript was recently published in the Journal of Immunology (Tarabishy et al). OLERF funds were also used to establish a BSL2 laboratory adjacent to the Pearlman lab to focus on this disease. These funds led directly to Dr. Pearlman obtaining a grant from the National Eye Institute to continue studies on this important pathogen.

Carlos Subauste, M.D., Associate Professor: OLERF funds were used to assist Dr. Carlos Subauste’s laboratory studies on the relevance of the cell surface receptor CD40 in two categories of retinal diseases: infectious retinopathies (using a model of ocular toxoplasmosis), and inflammatory retinopathies with a component of neurovascular degeneration (using a model of ischemic retinopathy associated with diabetic retinopathy). With funds provided by the OLERF, Dr. Subauste’s laboratory has demonstrated that mice that lack CD40 are susceptible to ocular toxoplasmosis. Dr. Subauste’s laboratory has developed lentiviral vectors that are currently being used to test the hypothesis that CD40 induces resistance against ocular toxoplasmosis by killing T. gondii via a novel cell mechanism termed autophagy. In addition, Dr. Subauste will use an animal model of toxoplasmic retinochoroiditis to explore the in vivo role of these signaling cascades with the goal to enhance control of this disease in patients via manipulation of intracellular signaling. This work has enabled Dr. Subauste to apply for an RO1 through the NEI.

Carlos Subauste, M.D Using a model of ischemia/reperfusion (I/R)-induced retinopathy, Dr. Subauste’s laboratory observed that CD40 is an important regulator of inflammation and neuro-vascular degeneration in the retina. CD40-/- mice subjected to retinal I/R do not develop retinal inflammatory infiltrates or capillary degeneration, and are protected against the loss of ganglion cells. Dr. Subauste’s laboratory is currently conducting studies on the mechanisms by which CD40 control inflammation and neuro-vascular degeneration in the retina. In addition, Dr. Subauste’s laboratory has developed a new approach to block intracellular signaling induced by CD40 that may prove effective to prevent inflammation and neuronal loss in retinopathies. OLERF funding was used to generate preliminary data that can be used to apply for NEI funding.

Ram Nagaraj, Ph.D., Carl Asseff, Jr. Professor: OLERF funds were used for technical support for the following projects: Cataract research: Dr. Nagaraj’s lab generated transgenic mouse lines some of which develop cataract within three months of birth, and is studying the biochemical mechanisms that underlie cataract formation, including the role of toxic kynurenines, He is also studying the role of glyoxalase I in cataract formation using a transgenic animal line that over-expresses glyoxalase I. and plan to investigate the role of this enzyme in cataract formation in diabetes. Diabetic retinopathy research: Retinal capillary cells die in the early phases of diabetic retinopathy. This leads to capillary occlusion, hypoxia and eventually to formation of new fragile blood vessels that leak blood into vitreous. Dr. Nagaraj’s lab have identified two proteins in retinal capillary cells that are down-regulated in the presence of high concentrations of glucose, and is developing peptide-based methods to prevent retinal capillary cell death in diabetic retinopathy.

Johnny Tang, M.D. Assistant Professor: OLERF departmental funds were important in the recruitment of Dr Tang who joined our department in July, 2007 and is working on age related macular degeneration (AMD) which is the most significant cause of visual loss in patients over the age of 65. To date, the search for therapies for AMD has been stymied due to a lack of a good animal model for AMD. Fortunately AMD is similar molecularly to other diseases for which we do have improved animal models including Leber's, Stargardt's disease and retinitis pigmentosa. The central  hypothesis of Dr. Tang’s studies is that a majority of these retinal diseases share common problems in their pathways of retinoid flow and rhodopsin metabolism. If we can understand the pathways and find treatments with this group of diseases with better animal models, the results may be universally applicable to other diseases in this group. There is a generalized deficit in the knowledge of cone physiology and pathophysiology compared to rod physiology. In modern day living, humans are more reliant on cone function than rod function. We will need to gain a better understanding of cone physiology in order to begin to treat patients with retinal degenerations. Dr. Tang’s research will examine cone physiology and will identify pharmacological targets and agents for treating patients with debilitating inherited and acquired retinal diseases. More progress in this area will provide hope that multiple retinal diseases will soon be treated by pharmaceutical intervention. Dr Tang currently has a career development grant from the Veterans’ Administration

Paul Park, PhD. Assistant Professor: OLERF departmental funds were important in the recent recruitment (July 1, 2008) to the Department. Dr Park’s research interests are in understanding the action of rhodopsin, which is the light receptor that initiates phototransduction and vision in the retina. Rhodopsin has a fundamental role in the initial events of vision, and mutations in this receptor cause blinding disease. A significant number of mutations in rhodopsin have been determined are directly linked to vision-related diseases such as retinitis pigmentosa and congenital night blindness. To tackle this objective, the candidate will utilize his background in receptor biology combined with the development of emerging nanotechnologies and biophysical approaches. With a clearer mechanistic understanding of the system in and the function and dysfunctions in the visual system can more readily and accurately be understood, which will result in improved and novel therapeutic approaches to combat retinal disorders. Dr. Park currently has a NEI grant that will support these goals.

Irina Pikuleva, PhD, Professor: Dr. Pikuleva is a well-established, senior investigator in cholesterol metabolism, who recently received NEI funding to examine the role of cholesterol in retinal degeneration. She will join our department in October, 2008, and work together with other investigators in retinal degeneration. Again, OLERF funds were involved in recruiting Dr Pikuleva, and will be used to help establish her program here at Case Western Reserve University.

Tadeo Maeda, M.D. Instructor: Dr Maeda joined our Department in November, 2007 with support from OLERF funds. His research is focused on Stargardt’s disease, which is the most common form of juvenile onset macular degeneration caused by the death of photoreceptor cells in the macula. Dr. Maeda will examine the mechanisms of photoreceptor cell death, with the goal of identifying potential targets for therapy for this devastating disease. OLERF funds will be used in part to assist Dr Maeda’s program.

Jonathan Lass, M.D. Charles I Thomas Professor and Chairman: Dr. Lass is the PI on the R21 Vision Research Coordinating Center (VRCC) Infrastructure grant. Dr. Lass’major effort this year has been as co-PI on the NEI-funded Fuchs’ Endothelial Corneal Dystrophy Genetics Multi-Center study. To date nearly 400 families and 1000 subjects at 30 sites around the country have been entered into the study with plans to complete enrollment by this fall. He is also now leading an effort to add 500 age matched subjects with normal corneas for a case control genetic analysis as well. Funds from the unrestricted grant of RPB were used for the pilot study that refined the phenotype grading system for the disease. The ultimate goal is to define the gene(s) that influence the development of the disease that could lead to novel strategies to prevent or treat the endothelial dysfunction in the disease.

Loretta Szczotka-Flynn, O.D., M.S., Associate Professor: OLERF funds were used to assist Dr. Szczotka-Flynn's research interests in keratoconus, and in the immunology and epidemiology surrounding contact lens related corneal infiltrates. Together with Sudha Iyengar, PhD from the CWRU Department of Epidemiology and Biostatistics, Dr. Szczotka-Flynn submitted a proposal to the NIH for a full scale, multi-center study on the genetic causes of keratoconus susceptibility. The long-term objectives of her work are to: identify the gene(s) that may contribute to the disease and to better understand the underlying mechanisms that cause the corneal thinning and scarring. RPB support was critical in funding parts of the additional pilot studies performed to generate data for the second full scale proposal. Dr. Szczotka-Flynn has also continued her training in epidemiology through her K23 NIH sponsored clinician scientist award. She is focusing on inflammatory complications associated with extended wear of silicone hydrogel contact lenses. She is collaborating with Eric Pearlman PhD and Mahmoud Ghannoum PhD on the role of biofilms in corneal infections and inflammation. Three papers acknowledging OLERF support were published in the last year on the topic of infiltrates, contact lenses, and biofilms on soft lenses.

mouse model of ocular onchocerciasis (river blindness). Parasite Immunology 2007,

Dependent on TLR4 and IL-1R1 but Not TLR21. The Journal of Immunology 2008,

12. Daehnel, K., Hise, A.G., Gillette-Ferguson, I., and Pearlman, E. Wolbachia and

Onchocerca volvulus: Pathogenesis of River Blindness. Issues Infect Dis. Basel,

18. Szczotka-Flynn, L., Debanne, S.M., Cheruvu, V.K., Long, B., Dillehay, S., Barr, J.,

W. R. Bryan Diabetic Eye Disease Research Fund