Diabetes damages the retina, and the resulting diabetic retinopathy (DR) is the leading cause of visual impairment and blindness in working-aged adults. Despite this, the pathogenesis of DR is poorly understood. Research done by us and others strongly implicates inflammatory processes in the development of the critical microvascular lesions of DR, and work done during our current Merit research demonstrates that the induction of these inflammatory proteins by hyperglycemia is regulated by protein acetylation. The central hypothesis of our current proposal is that increased acetylation of proteins in diabetes contribute to the degeneration of retinal capillaries via inflammatory pathways, and that leukocytes in particular play a critical role in the pathogenesis of this acetylation-driven degeneration of retinal capillaries. Using 2 models of DR (streptozotocin to induce a Type 1 diabetes, and spontaneously diabetic db/db mice which are a model of Type 2 diabetes), research in this proposal will determine if inhibition of this acetylatin systemically (Aim 1) or in leukocytes only (Aim 2) inhibits development of the characteristic vascular lesions of early DR. These studies will be performed both as prevention trials and as intervention trials.
The third aim of this proposal will extend these studies to patients, using leukocytes from Veterans (both diabetic and nondiabetic) to determine if leukocyte- mediated killing of retinal endothelial cells in diabetes can be prevented by inhibiting or reversing acetylation of proteins in leukocytes. We also will begin to explore if the extent of acetylation-mediated killing of retinal endothelial cells by leukocytes from diabetic patients correlates with the severity of retinopathy and might predict which patients are most susceptible to develop advanced DR.
Diabetic retinopathy is a leading cause of vision loss in working-age adults in industrialized nations, but its pathogenesis remains unclear. Evidence that inflammation contributes to the retinopathy is accumulating, but the molecular cause of this inflammation is still under investigation. We have demonstrated that histone acetylation in elevated glucose regulates induction of inflammatory proteins, and we will now test if inhibition of this increased acetylatio of proteins in diabetes can inhibit lesions of early diabetic retinopathy.
|Kern, Timothy S (2017) Do photoreceptor cells cause the development of retinal vascular disease? Vision Res 139:65-71|
|Tonade, Deoye; Liu, Haitao; Kern, Timothy S (2016) Photoreceptor Cells Produce Inflammatory Mediators That Contribute to Endothelial Cell Death in Diabetes. Invest Ophthalmol Vis Sci 57:4264-71|
|Liu, Haitao; Tang, Jie; Du, Yunpeng et al. (2016) Photoreceptor Cells Influence Retinal Vascular Degeneration in Mouse Models of Retinal Degeneration and Diabetes. Invest Ophthalmol Vis Sci 57:4272-81|
|Du, Yunpeng; Cramer, Megan; Lee, Chieh Allen et al. (2015) Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability. FASEB J 29:2194-204|
|Veenstra, Alexander; Liu, Haitao; Lee, Chieh Allen et al. (2015) Diabetic Retinopathy: Retina-Specific Methods for Maintenance of Diabetic Rodents and Evaluation of Vascular Histopathology and Molecular Abnormalities. Curr Protoc Mouse Biol 5:247-70|
|Liu, Haitao; Tang, Jie; Du, Yunpeng et al. (2015) Retinylamine Benefits Early Diabetic Retinopathy in Mice. J Biol Chem 290:21568-79|
|Saliba, Alexandra; Du, Yunpeng; Liu, Haitao et al. (2015) Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice. PLoS One 10:e0139003|
|Kern, Timothy S; Berkowitz, Bruce A (2015) Photoreceptors in diabetic retinopathy. J Diabetes Investig 6:371-80|