Aging and Diabetes

Dr. Ram H. Nagaraj's laboratory studies biochemical mechanisms of cataract, specifically the role of Maillard reactions and oxidation in cataractogenesis, and diabetic retinopathy, specifically the role of oxidative stress.   His research on cataract is to understand how sugars, sugar metabolites and vitamin-C can chemically modify lens proteins and how such modifications can alter their structure and function. He uses lens epithelial cells to study relationship of oxidative stress and the formation of sugar metabolites that occur during lens aging and cataract formation.  He also has been examining the chaperone function of small heat shock proteins and their chemical modification by methylglyoxal and effect on their anti-apoptotic functions. Dr. Nagaraj’s laboratory’s second project is on diabetic retinopathy. The focus of this project is to understand at the biochemical and molecular level mechanisms of capillary cell death in diabetes. These studies are being conducted in human and bovine retinal capillary cells.

-Dr. Tim Kern’s laboratory conducts numerous studies examining the early events and the development of new therapeutic strategies in diabetic retinopathy in rodent and porcine models. He serves as the Director of Diabetes Research in the Division of Endocrinology of the Department of Medicine.  His studies into diabetic retinopathy are diverse and include 1) the effects of experimental therapies, including PARP inhibitors and anti-inflammatory agents on the development of retinal microvascular lesions in diabetic rats and mice; 2) hyperglycemia-induced alterations in glucose accumulation and expression of the glucose transporter, Glut-1, in nitric oxide production and effects on cellular metabolism, and in activation of proteolytic caspases; and 3) alterations in retinopathy and other complications of diabetes in genetically altered mice (for example,  overexpressing BCl-1 and lacking the p105 subunit of NF-kB).

-Dr. Susanne Mohr’s lab is focused on the role of hyperglycemia-induced caspase activation and subsequent apoptosis of retinal cells with major emphasis on Müller cells. Her laboratory is adjacent to Dr. Kern’s in the BRB where she is a member of the Division of Endocrinology’s diabetes research group, particularly working closely with Dr. Kern.  The questions she has been recently addressing include:  (1) what role do caspases play in the development of diabetic retinopathy, (2) how does hyperglycemia activate caspases and are there cell type specific caspase signaling pathways, (3) is caspase-1 involved in inflammatory processes or does it act as an apoptosis initiator, and (4) are caspases suitable as therapeutic targets.  Experiments are conducted in vivo and in vitro using diabetic and galatosemic mice.

Contact Lens Research

Contact lens research spans industry funded clinical trials on high oxygen silicone hydrogel lenses for 30 days continuous wear, to contact lens solution and rewetting drop studies.  Additionally, a major study aimed at achieving a better scientific understanding of the factors and mechanisms of inflammatory and mechanical complications of silicone hydrogel continuous wear contact lens use is being performed by Dr. Szczotka-Flynn.  The LASH Study is NEI funded and will test the hypothesis that complement activation and regulation coupled with bacterial contamination of lenses and the ocular surfaces are risk factors for contact lens associated inflammatory complications.  Additionally, this project will test the hypothesis that novel quantitative central and peripheral corneal shape descriptors, measured by corneal topography, are associated with mechanical complications during long term wear of silicone hydrogel lenses.  224 patients will be enrolled and followed for 18 months in this longitudinal cohort study.

Ocular Immunology

Since the initial submission, Dr. Pearlman’s laboratory now has three active projects examining corneal inflammation in relation to onchocerciasis and bacterial keratitis. Firstly, using a murine model for ocular onchocerciasis, in which soluble parasite antigens are injected into the corneal stroma, his NIH funded studies examine the role of endosymbiotic Wolbachia bacteria in inflammatory responses in the cornea. This project has already resulted in a paper in Science [Science 295:1892.2002].  Dr. Pearlman’s second NIH project is examining the role of Toll Like receptors as part in the innate immune response in the cornea to bacterial products such as endotoxin, peptidoglycan and bacterial DNA.  Dr. Lass, Center Director, is a collaborator on both of these grants.   Dr. Pearlman’s third study, which is sponsored by Bausch and Lomb, Inc., is to develop anti-inflammatory reagents for corneal inflammation associated with complications resulting from contact lens wear.

Dr. Edward Medof’s laboratory studies focus on cell surface regulatory proteins that function in the plasma membrane of self-cells to prevent autologous complement activation on their surfaces.   The proteins he studies include the decay accelerating factor (DAF), the membrane cofactor protein (MCP), and the membrane inhibitor of reactive lysis (MIRL or CD59).  He has developed murine knockouts of each to study their physiological importance in the eye in vivo.  Because of remarkable preliminary data on a possible role of DAF in ocular myasthenia gravis, Dr. Medof’s lab will play an essential role along with his colleagues Drs. Stahl and Porter in the Department of Neurology, and Dr. Hoppel in the Department of Pharmacology, in their studies of the recently awarded R24 grant to Dr. Kaminski to develop a new therapy for this crippling disease. 

Ocular Genetics

Dr. Iyengar’s laboratory conducts numerous studies to locate genes for ocular traits and disorders such as age-related macular degeneration, age-related cataract, Fuchs’ dystrophy, keratoconus and diabetic retinopathy.  Besides laboratory work, Dr. Iyengar is also responsible for creation of databases for large-scale studies.  Programmers and other staff in her group conduct bioinformatic mining of public databases as well as experimental data for genetic and genomic studies.