Proliferative diabetic retinopathy and the fibrocontractive processes that cause retinal detachment are ultimately cellular diseases in that they arise from the activities of individual cells. Muller cells, the principal glia of the retina, are physically associated with fibrocontractive tissues in diabetes. Further, recent studies indicate that Muller cells are capable of generating tractional forces and that this activity is stimulated by insulin-like growth factor I (IGF-1), a growth factor whose biological activity is significantly elevated in diabetic vitreous. Thus, the study of Muller cells responses to IGF-1 are of immediate relevance to the pathogenesis of proliferative diabetic retinopathy. Interestingly, diabetes-related increases in vitreous IGF-1 activity cannot be explained by higher growth factor concentrations alone. IGF-1 is normally present in vitreous at biologically active concentrations, but growth factor activity cannot be detected, suggesting that other diabetes-related changes result in increased IGF-1 bioavailability or enhanced growth factor sensitivity in the target cells. Effects of these types have been reported for members of the insulin-like growth factor binding protein family (IGFBPs). Consistent with this, the normal vitreous complement of IGFBPs changes dramatically in diabetes. We propose that diabetes-associated changes in vitreous IGFBPs rather than IGF-1 are the principal cause of higher growth factor activity. Unfortunately, our current understanding of IGFBP effects do not extend to Muller cells or IGF-1 induced fibrocontractive processes. This application proposes five lines of investigation to analyze this relationship including studies to determine (1) if Muller cells are a source of vitreous IGFBPs in diabetes, (2) if Muller cells have the capacity to modulate IGFBP activity through secreted proteases, (3) the effects of IGFBPs have on IGF-1 biological activity with respect to Muller cells, (4) if IGFBPs have direct, growth factor-independent effects on Muller cells and )5) if Muller cell activities are supported in an animal model of diabetes. The information gained from this study will not only improve our understanding of fibrocontractive processes, but should represent a significant gain toward control of this blinding complication of diabetic retinopathy.
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