Ram H. Nagaraj, Ph.D.
Carl F. Asseff, M.D. Professor of Ophthalmology & Visual Sciences and Pharmacology
Department of Ophthalmology & Visual Sciences
Institute of Pathology, 311
2085 Adelbert Road
Cleveland, Ohio 44106
Phone : 216-368-2089
Dr. Ram H. Nagarajís laboratory investigates two major complications of the eye: cataract and diabetic retinopathy. In a recent study they have demonstrated that α-crystallin becomes a better chaperone after modification by methylglyoxal, a dicarbonyl compound present in the human lens. They have identified specific arginine modifications that may be responsible for the enhanced chaperone function. Site directed mutagenesis experiments have shown that arginine21 plays a major role in determining the strength of the chaperone function. Studies are in progress to investigate the effect of methylglyoxal modification on the anti-apoptotic properties of small heat shock proteins. In another project, they are investigating the role of glyoxalase and other dicarbonyl metabolizing enzymes on regulation of protein modification in aging lenses. The third project focuses on the role of trypotophan oxidation products in lens protein modifications. Specific monoclonal antibodies are being generated to detect such modification in the human lens.
The project on diabetic retinopathy is to investigate the effects of dicarbonyl stress on retinal capillary cell functions and apoptosis. Dicarbonyl stress occurs as a consequence of hyperglycemic stress in diabetes. They have recently concluded a study in which they have demonstrated that methylglyoxal and glyoxal modified fibronectin causes apoptosis of bovine retinal capillary pericytes. Such apoptosis seem to occur because of an increase in oxidative stress, changes in integrin-mediated signal transduction, actin fragmentation and loss of αβ-crystallin. They have shown that overexpression of αβ-crystallin prevents apoptosis of pericytes. This is the first demonstration of αβ-crystallin in pericytes and its possible role in apoptosis under conditions of hyperglycemia. They are currently investigating mechanisms by which αβ-crystallin inhibits apoptosis of pericytes. In another recent study, they have demonstrated that glyoxalase I is critical for the survival of pericytes under high glucose conditions. Its downregulation and inactivation by nitric oxide appears to enhance high glucose-induced apoptosis of pericytes. Human retinal pericytes are being used in these studies.