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

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.

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.

OLERF has been instrumental in supporting the growth of the Department and the

VSRC by providing pilot funds for new projects, supplemental funds for Department of

Ophthalmology investigators to support post-doctoral fellows, and has been used towards

equipment for investigators in the new facility, specifically for a project on fungal keratitis

that will be critical for the work of Drs. Pearlman and Carlson. As the Department of

Ophthalmology and Visual Sciences has continued to grow and develop, we have focused

on four major research themes:

Subauste.

Page 3 of 9

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

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

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’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

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.

Page 4 of 9

Subauste’s laboratory observed that CD40 is an important regulator of inflammation

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.

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. 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.

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

Page 5 of 9

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

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

hand 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.

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.

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.

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

Page 6 of 9

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.

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.

In the coming year, we propose to utilize OLERF funds to support part of the programs of all

of these researchers in the four areas described above. In particular, the newly formed

Retinal Degeneration investigators may require common equipment and other resources

that will be used to enhance these research programs. OLERF funds will also be used to

help equip laboratory space for working with pathogens that cause ocular diseases (Ocular

Infectious Diseases Program).

Page 7 of 9

A. CONFERENCES

February, 2008. Department of Ophthalmology, University of California at Irvine.

September, 2008. Symposium speaker, International Congress for Eye Research, Beijing,

China

B. INVITED SPEAKER

August, 2007. Symposium speaker, Contact Lens Society, Whistler, British Columbia

September, 2007. Symposium speaker. Tear Film and Ocular Surface Society, Taormina,

Sicily.

October, 2007. Symposium speaker, Cullen Eye Institute Conference, Houston, TX

January, 2008. Invited Speaker, Bascom Palmer Eye Institute, Miami, FL.

March, 2008. Invited Speaker, University of Athens Department of Infectious Diseases

April, 2008. Invited Speaker, Penn State University, Hershey, PA, Department of

Pharmacology

December, 2008. Invited speaker Scheppens Eye Institute, Boston, MA

Page 8 of 9

1. Carlson, E.C., Lin, M., Liu, C., Kao, W., Perez, V.L., and Pearlman, E. .Keratocan and

Lumican Regulate Neutrophil Infiltration and Corneal Clarity in Lipopolysaccharide-induced

Keratitis by Direct Interaction with CXCL1. The Journal of Biological Chemistry 2007. 282-

49:35502-35509.

2. Meij, J.,Carlson, E.C., Wang, L., Liu, C., Jester, J.V., Birk, D.E., Kao, W. Targeted

expression of a lumican transgene rescues cornealdeficiencies in lumican-null mice.

Molecular Vision 2007. 13:2012-8.

3. Adhikary, G., Sun, Y., and Pearlman, E. C-Jun NH2 terminal kinase (JNK) is an

essential mediator of Toll-like receptor 2-induced corneal inflammation. Journal of

Leukocyte Biology 2008. 83:991-997

4. Chinnery, H.R., Pearlman, E., and McMenamin, P.G. Cutting Edge: Membrane

Nanotubes In Vivo: A Feature of MHC Class II. Cells in the Mouse Cornea The

Journal of Immunology, 2008, 180: 5779 –5783.

5. Chinnery, H.R., Humphries, T., Clare, A., Dixon, A.E., Howes, K., Moran, C.B., Scott,

D., Zakrzewski, M., Pearlman, E., and McMenamin, P.G. Turnover of bone marrowderived

cells in the irradiated mouse cornea. Immunology 06/ 2008; 1-8.

6. Daehnel, K., Gillette-Ferguson, I., Hise, A.G., Diaconu, E., Harling, M.J., Heinzel,

F.P., and Pearlman, E. Filaria/ Wolbachia activation of dendritic cells and

development of Th1-associated responses is dependent on Toll-like receptor 2 in a

29: 463–473.

7. Gillette-Ferguson, I., Daehnel,K., Hise, A.G., Sun, Y.,Carlson, E., Diaconu,E.,

McGarry, H.F., Taylor, M.J., and Pearlman, E. Toll-Like Receptor 2 Regulates CXC

Chemokine Production and Neutrophil Recruitment to the Cornea in Onchocerca

volvulus/ Wolbachia-Induced Keratitis. Infection and Immunity 2007. 75.12; 5908–

5915.

8. Lin, M., Jackson, P., Tester, A.M., Diaconu, E., Overall, C.M., Blalock, J.E., and

Pearlman, E. Matrix Metalloproteinase-8 Facilitates Neutrophil Migration through the

Corneal Stromal Matrix by Collagen Degradation and Production of the Chemotactic

Peptide Pro-Gly-Pro. The American Journal of Pathology 2008. Vol. 173.1, 144-153.

9. Tarabishy, A.B.,Aldabagh, B., Sun,Y., Imamura, Y., Mukherjee, P.K.,Lass, J.H.,

Ghannoum, M.A., and Pearlman, E. MyD88 Regulation of Fusarium Keratitis Is

181: 593-600.

10. Imamura, Y., Chandra, J., Mukherjee, P.K., Lattif, A.A., Szczotka-Flynn, L.B.,

Pearlman, E., Lass, J.H., O’Donnell, K., and Ghannoum, M.A. Fusarium and

Candida albicans Biofilms on Soft Contact Lenses: Model Development, Influence of

Lens Type, and Susceptibility to Lens Care Solutions. Antimicrobial Agents and

Chemotherapy 2008. 52.1;171–182

11. Johnson, A.C.,Li, X., and Pearlman, E. MyD88 Functions as a Negative Regulator of

TLR3/TRIF-induced Corneal Inflammation by Inhibiting Activation of c-Jun N-terminal

Kinase. The Journal of Biological Chemistry 2008. 283.7; 3988–3996.

Karger, 2007, 5, 133–145.

13. Biswas, A.,Wang, B.,Miyagi,M., and Nagaraj, R.H. Effect of methylglyoxal

modification on stress-induced aggregation of client proteins and their chaperoning

by human áA-crystallin. Biochem. J. (2008) 409, 771–777

14. Biswas A, Lewis S, Wang B, Miyagi M, Santoshkumar P, Gangadhariah MH, Nagaraj

RH. Chemical Modulation of the Chaperone Function of Human {alpha}A-Crystallin. J

Biochem. 2008 Jul;144(1):21-32.

15. Staniszewska, M., Nagaraj, R.H. Detection of kynurenine modifications in proteins

using a monoclonal antibody. Journal of Immunological Methods 324 (2007) 63–73

16. Nagaraj, R.H., Biswas, A., Miller, A., Oya-Ito, T., and Bhat, M. The Other Side of the

Maillard Reaction. Ann. N.Y. Acad. Sci. 1126: 107–112 (2008

17. Szczotka-Flynn, L., and Diaz, M. Risk of Corneal Inflammatory Events with Silicone

Hydrogel and Low Dk Hydrogel Extended Contact Lens Wear: A Meta-Analysis

Optometry and Vision Science, Vol. 84, No. 4, April 2007

Bergenske, P., Donshik, P., Secor, G, and Yoakum, J. Predictive Factors for Corneal

Infiltrates with Continuous Wear of Silicone Hydrogel Contact Lenses. Arch

Ophthalmol. 2007;125:488-492

19. Sun, Y., Fox, T., Adhikary, G., Kester, M., and Pearlman, E. Inhibition of corneal

inflammation by liposomal delivery of short-chain, C-6 ceramide. Journal of

Leukocyte Biology June 2008 Volume 83: 1512-1521.