The Effects of Hyperglycemia on Visual System Development

Maternal diabetes is known to increase the risk of birth defects in the central nervous, cardiovascular, and musculoskeletal systems, and is also associated with long-term metabolic and cognitive effects in children and adolescents. The developing fetal visual system is also sensitive to changes in the intrauterine environment, however very little data exists on the impact of maternal diabetes on ocular morphogenesis and retinal development. This information may be critical for the early identification and treatment of visual deficits in infants of diabetic mothers. In this pilot proposal, we will address these gaps in our knowledge using the zebrafish and mouse model systems to investigate the consequences of hyperglycemia in the embryonic retina. Two specific aims are proposed: Specific Aim 1: Determine the consequences of hyperglycemia on the developing retina at the cellular and molecular level using the zebrafish model a) We will use in vivo time-lapse imaging to determine the effects of differing glucose levels during embryogenesis on ocular morphogenesis and retinal development b) We will determine the effects of hyperglycemia on retinal progenitor cell proliferation, survival, and differentiation, and on the formation of the optic nerve c) We will investigate the effects of hyperglycemia on insulin/IGF signaling and gene expression programs within the developing retina Specific Aim 2: Determine the consequences of maternal hyperglycemia on pre- and post-natal retinal development in a mouse model of gestational diabetes (the db/+ mouse) a) We will determine how gestational diabetes affects the differentiation of retinal neurons b) We will investigate the effects of gestational diabetes on insulin signaling in the developing retina The results of our study will provide solid preliminary data and a validated model system with which to further investigate the cellular and molecular mechanisms of diabetes-induced developmental retinal pathologies.