Investigating the Molecular Mechanism of Hexose-induced Stress in Lens and Retina

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DESCRIPTION: Diabetes is a rapidly increasing public health problem. Inadequate control of hyperglycemia leads to the onset and progression of the "late complications" of diabetes mellitus which in the eye include cataract and diabetic retinopathy, both of which result in vision loss. Previous studies with diabetic and galactosemic animals have demonstrated that both sugar cataract formation and retinal vascular alterations associated with diabetic retinopathy are linked to osmotic and oxidative stress associated with excess aldose reductase activity through the polyol pathway. Excess aldose reductase activity has also been linked to signal transduction changes, cytotoxic signals and activation of apoptosis. Preliminary studies also indicate that aldose reductase activity is linked to stress-related gene expression changes. In this grant application, we propose to elucidate the mechanism(s) by which aldose reductase activity and hexose-induced oxidative stress in the lens and retina are linked to altered ocular levels of insulin-like growth factor (IGF), transforming growth factor (TGF-beta) and basic fibroblast growth factor (b-FGF), three growth factors observed to be involved in cataract formation and diabetic retinopathy. The levels of MAPK, PI-3K, SMAD3 in the signaling pathways of IGF and TGF-beta and the apoptotic factors, caspase 3, p53, and p38 will be assessed. In addition, the major target genes of IGF, TGF-beta , and b-FGF signaling pathways will be identified using the Fox (IGF1), SMAD3 or 4 (TGF-p), or SAPK/JNK (b-FGF) transcriptional factors with microarray analysis. These studies will be conducted in diabetic and galactose-fed rats and in normal and transgenic mice in which the retinal pericytes contain increased levels of aldose reductase. By clarifying the source of this hexose-linked oxidative stress and identifying the specific mechanism(s) through which aldose reductase alters the ocular levels of b-FGF, IGF and TGF-beta, their associated signaling pathways and gene expression, new insights into the treatment for cataract and diabetic retinopathy can be obtained. Moreover, these studies should help identify new drug targets for the treatment of these diabetic complications.