The Insulin-Like Growth Factor System and Muller Cells

描述（由申请人提供）：最终，引起视网膜脱离的退行性糖尿病视网膜病变和纤维收缩过程是细胞疾病，因为它们是由单个细胞的不同活动引起的。米勒细胞是主要的视网膜神经胶质细胞，与纤维血管瘢痕有物理联系，能够产生导致视网膜脱离的牵引力。来自该实验室和其他实验室的最新研究表明，两种基本的Muller细胞活性，增殖和牵引力产生，受到胰岛素样生长因子的刺激，并且最近的研究表明，玻璃体胰岛素样生长因子活性在糖尿病中升高。有趣的是，糖尿病相关的玻璃体胰岛素样生长因子活性的增加不能单独用生长因子浓度的增加来解释，这表明涉及更复杂的机制。我们的研究胰岛素样生长因子结合蛋白对胰岛素样生长因子刺激的Muller细胞的影响表明，在正常条件下，玻璃体胰岛素样生长因子结合蛋白可以作为生长因子汇，糖尿病相关的变化有助于胰岛素样生长因子活性的净增加。这些研究还越来越强调胰岛素样生长因子结合蛋白-3的参与，胰岛素样生长因子结合蛋白-3是玻璃体中丰富的结合蛋白，也是胰岛素样生长因子作用的最有效抑制剂。目前的研究考虑了胰岛素样生长因子结合蛋白-3的玻璃体特异性修饰，这些修饰对生物活性的影响，胰岛素样生长因子结合蛋白调节纤维增生反应的能力以及糖尿病中玻璃体生长因子活性的起源。从这项研究中获得的信息将提高我们对纤维收缩性视网膜疾病的理解，并应代表对控制与糖尿病视网膜病变相关的增殖性并发症的重大收获。

DESCRIPTION (provided by applicant): Proliferative diabetic retinopathy and the fibrocontractive processes that cause retinal detachment are, in the end, cellular diseases in that they arise from the varied activities of individual cells. Muller cells, the principal retinal glia, are physically associated with fibrovascular scar and are capable of generating tractional forces of the type that cause retinal detachment. Recent studies from this and other laboratories indicate that two essential Muller cell activities, proliferation and tractional force generation, are stimulated by insulin-like growth factors and more recent studies indicate that vitreous insulin-like growth factor activities are elevated in diabetes. Interestingly, diabetes-associated increases in vitreous insulin-like growth factor activities cannot be explained by increases in growth factor concentration alone, suggesting the involvement of more complex mechanisms. Our studies of insulin-like growth factor binding protein effects on insulin-like growth factor-stimulated Muller cells suggest that vitreous insulin-like growth factor binding proteins can, under normal conditions, function as a growth factor sink and that diabetes-associated changes contribute to net increases in insulin-like growth factor activities. These studies also place increased emphasis on the involvement of insulin-like growth factor binding protein-3, an abundant binding protein in vitreous and the most effective inhibitor of insulin-like growth factor effects. The current study considers vitreous-specific modifications to insulin-like growth factor binding protein-3, the effects of these modifications on biological activities, the ability of insulin-like growth factor binding proteins to regulate fibroproliferative responses and the origins of vitreous growth factor activities in diabetes. Information gained from this study will improve our understanding of fibrocontractive retinal diseases and should represent a significant gain toward control of proliferative complications associated with diabetic retinopathy.