CASE WESTERN RESERVE UNIVERSITY
DEPARTMENT OF OPHTHALMOLOGY
AND VISUAL SCIENCES
OHIO LIONS EYE RESEARCH FOUNDATION
Continuation Grant Application, 2011
Jonathan H. Lass, M.D., Charles I Thomas Professor and Chairman
Eric Pearlman, Ph.D., Professor and Director of Research
OLERF funds continue to be utilized by our research faculty and post-doctoral fellows to advance the vision research program in the Department of Ophthalmology. With the help of these funds, several papers have been published in the last year, most of which are in high profile journals. In addition, research funded in part by OLERF was used for pilot projects as the basis for other grant applications and for equipment purchase. Our research faculty in the Department comprises Drs. Akiko Maeda (recently promoted to Assistant Professor), Tadeo Maeda, Ram Nagaraj, Paul Park, Eric Pearlman and Irina Pikuleva. OLERF funds also partly support the clinical research programs of Jonathan Lass, MD, and Loretta Sczcotka-Flynn, OD, PhD. Faculty with secondary appointments include Drs. Tim Kern and Carlos Subauste (Department of Medicine), Dr Sudha Iyengar (Epidemiology) and Dr Masaru Miyagi (Proteomics). Together with vision researchers in other departments at CaseWestern Reserve University, notably in the Department of Pharmacology under Dr Palczewski, the vision research group now comprises sixteen faculty members. There are numerous collaborations among the investigators in addition to seminar series and an annual symposium that ensures a continued and exciting research environment.
The same major research themes are presented as last year:
1) Retinal function and retinal degeneration: Drs. Akiko and Tadeo Maeda, Miyagi, Park, Pikuleva, and Tang
2) Aging and Diabetes: Drs. Nagaraj, Kern and Subauste
3) Ocular Immunology, Infection and Inflammation: Drs. Pearlman and Subauste
4) Molecular epidemiology of corneal disease: Drs. Lass, Szczotka-Flynn and Iyengar
1) Retinal degeneration
Akiko Maeda, M.D., PhD, Assistant Professor: OLERF funds are still being used in Dr Akiko Maeda’s research. She has an NEI Career Development award to work on animal models of age related macular degeneration (AMD), and is collaborating with Dr Palczewski on a large NEI funded project pharmacological interventions in retinal degenerations. In collaboration with Dr Pearlman, she published a paper on the role of the host immune system in AMD. Dr Maeda was promoted to Assistant Professor this year, and will apply for a larger NEI grant later this year.
Tadeo Maeda, M.D., PhD, Senior Instructor: OLERF funds were important for Dr Tadeo Maeda’s work on a different mouse model of AMD, which led to his being awarded a KO8 Career Development award from NIH. He is focused on a genetics approach to identify novel genes associated with retinal disease, and is collaborating with investigators in the Department of Genetics.
Paul Park, PhD. Assistant Professor: The goal of Dr. Park’s laboratory is to understand the structure and function of rhodopsin and the mechanism of signal transmission in phototransduction as it relates to human retinal dystrophies. Dr. Park employs sophisticated modern biophysical approaches to answer molecular questions and include atomic force microscopy (AFM), single-molecule force spectroscopy (SMFS), and fluorescence resonance energy transfer (FRET). In the past year, OLERF funds were used to explore emerging paradigms that provide critical updates to our traditional views of how this system functions. These experiments are providing a very accurate description of the system and will allow a better assessment of dysfunctional states observed in disease. The laboratory is currently interested in understanding how single mutations in rhodopsin can cause a wide variety of retinal dystrophies ranging from night blindness to retinitis pigmentosa. Studies will also provide insights into why excessive activation of rhodopsin, either by mutation or excessive light exposure, can result in retinal degeneration as observed in inherited diseases such as retinitis pigmentosa and age-related macular degeneration.
Irina Pikuleva, PhD, Professor: Dr. Pikuleva’s laboratory is studying the role of cholesterol in the retinal in age related macular degeneration. During the past year, OLERF funds contributed to research that has led to identification of the unexpected link between cholesterol in the retina and the generation of new blood vessels. Studies of mice lacking one of the enzymes involved in retinal cholesterol removal (CYP27A1) revealed the formation of abnormal blood vessels in the retina and possible events triggering this phenomenon. These findings provide insights into the possible mechanisms whereby the link between retinal cholesterol and age-related macular degeneration is realized.
2) Aging and Diabetes:
Ram Nagaraj, Ph.D., Carl F. Asseff, M.D. Professor of Ophthalmology: OLERF funds were used for technical support for the following projects: Cataract research: A new mechanism of protein modification in the lens was identified. This mechanism known as “lysine acetylation” increases the protective function of α-crystallin, a major protein of the lens. Another study investigated the chemical mechanism of glycation (a protein modification reaction) in the lens and identified a new intermediate of the reaction. This intermediate was quantified using a novel method. A paper on these findings has been accepted for publication in Archives of Biochemistry and Biophysics and another manuscript has been submitted for publication to Biochimica Biophysica Acta. Diabetic retinopathy research: Retinal Muller cells were found to express high levels of indoleamine 2,3-dioxygenase (IDO), an enzyme linked to capillary cells death in the diabetic retina. Current investigations are directed at understanding the regulation of expression of this enzyme by inflammatory cytokines and testing the role of IDO in experimental diabetic retinopathy in mice. One manuscript on these findings has been submitted to Diabetes and another being prepared for submission to Investigative Ophthalmology and Visual Science.
3) Ocular Immunology, Infection and Inflammation:
Eric Pearlman, Ph.D., Professor: Studies in Dr Pearlman’s lab focus on understanding the mechanisms underlying corneal inflammation and corneal infection, either as a consequence of contact lens wear or as a result of ocular trauma. Specifically, he is examining host immunity and microbial virulence factors that determine survival of the organisms in the cornea and the severity of corneal disease. In addition to supporting studies on bacterial and fungal keratitis, OLERF funds have been used to initiate a new are of research on Acanthamoeba keratitis. Acanthamoeba are protozoa that live in the water and plumbing systems and can cause a very painful and difficult to treat infection. The recent outbreak in Chicago and on the east coast has renewed interest in this disease by the CDC and NEI, and Dr Pearlman’s preliminary studies are in collaboration with clinicians and epidemiologists in Chicago and at Ohio State University. In the coming year, these OLERF supported studies will lead to at least three papers and submission of a new NEI grant.
4) Molecular epidemiology of eye diseases
Jonathan Lass, M.D. Charles I Thomas Professor and Chairman: Dr. Lass is the PI on the U10 supported Specular Microscopy Ancillary Study that is examining the effect of donor age on endothelial cell loss following penetrating keratoplasty for primary endothelial dysfunction conditions; the study is now in its 10th year of followup. Dr. Lass’ other major effort has been as co-PI on the NEI-funded Fuchs’ Endothelial Corneal Dystrophy Genetics Multi-Center study. Over 1500 families and 2000 subjects at 33 sites around the country have been entered into the study. Genetic analyses of these subjects corresponding to the extent of their disease in the cases and lack of disease in the controls is now underway working with NIH with data available by this fall. OLERF Funds 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. He is initiating a new study with Lions funds to examine the performance of a new corneal preservation medium, Life 4C as compared to the current medium, Optisol GS, in regards to graft success and endothelial cell loss following endothelial keratoplasty. The first subjects have been entered and recruitment should be concluded this fall with results available by the end of next year. Finally, Dr. Lass is the PI on a soon to be funded multi-center National Eye Institute sponsored trial that will involve the enrollment of 1330 patients at 30 clinical sites around the country and 20 eye banks examining whether transplant success and endothelial cell loss is comparable by extending the preservation time out to the FDA approved 14 days compared to corneas preserved out to 7 days which is the normal use of tissue in the United States. By proving that corneas can be successfully used out to 14 days, this will lead to expansion of the donor pool and more efficient use of the donor tissue.
Loretta Szczotka-Flynn, O.D., Ph.D., Associate Professor: OLERF funds were used to further Dr. Szczotka-Flynn’s research interests on contact lens related corneal infiltrates as well as mucin ball presence and association with infiltrative responses, which are a major concern for contact lens users. Dr. Szczotka-Flynn received Sponsored Research Awards from Alcon Laboratories and Johnson & Johnson Vision Care to identify risk factors for infiltrative responses. One of her areas of research are bacteria isolated on lenses and the host response in the tears of individuals using daily wear silicone hydrogel lenses. This work is being undertaken in collaboration with Dr. Eric Pearlman. She is also working on contact lens associated biofilms and efficacy of contact lens care solutions against such biofilms in conjunction with Dr. Pearlman and Mahmoud Ghannoum, PhD.
We will continue to use departmental OLERF funds to support many of these programs, especially projects that look promising for future NIH funding.