Professor, Director of Truhlsen Laboratory
Molecular biology of ocular aging
Dr. Toshimichi Shinohara and colleagues study the mechanisms of cataract formation in the eye and age-associated damage to the lens. Higher levels of glucose are found in diabetes patients, which develops cataract. Methylglyoxal (MGO) is a highly cytotoxic metabolite produced from glucose metabolism. The toxic effects are mediated through formation of MGO-adduct and advanced glycation end products, which contribute to aging and diabetic complications. But, evidence for the essential role of MGO-induced endoplasmic reticulum (ER) stress and epigenetic loss of Nrf2/Keap1 dependent antioxidant protection in diabetes is emerging. This study investigated the mechanism by which MGO induced the ER stress and by what epigenetic mechanisms MGO inactivated the Nrf2/Keap1 dependent antioxidant protection in lens epithelial cells (LECs) during cataractogenesis. Dr. Shinohara’s laboratory study revealed a possible mechanistic rationale by which MGO activates ER stress, failure of Nrf2/Keap1 dependent antioxidant system and altered expressions of DNA methylation and demethylation enzymes through proteosomal degradation. Also, epigenetic DNA modification of Keap1 promoter by MGO stimulates Keap1 expression, which increases proteosomal degradation of Nrf2. So, redox-balance is altered towards lens oxidation and cataract formation.
B.S., Shinshu University, Nagano-Ken, Japan
M.S., Tokyo Kyoiku University, Tokyo, Japan
Ph.D., Department of Biophysics Faculty of Science, Kyoto University, Kyoto, Japan
Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD
Laboratory of Vision Research, NEI, NIH, Bethesda, MD
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