The Insulin-Like Growth Factor System and Muller Cells

描述(申请人提供)：增殖性糖尿病视网膜病变和导致视网膜脱离的纤维收缩过程归根结底是细胞性疾病，因为它们是由单个细胞的不同活动引起的。穆勒细胞是主要的视网膜胶质细胞，在物理上与纤维血管瘢痕有关，并能够产生导致视网膜脱离的牵引力。最近来自该实验室和其他实验室的研究表明，胰岛素样生长因子刺激了两种基本的米勒细胞活动，即增殖和牵引力的产生，而最近的研究表明，糖尿病患者玻璃体胰岛素样生长因子的活性增加。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仅用生长因子浓度的增加来解释，这表明参与了更复杂的机制。我们对胰岛素样生长因子刺激的Muller细胞的胰岛素样生长因子结合蛋白影响的研究表明，在正常情况下，玻璃体胰岛素样生长因子结合蛋白可以起到生长因子汇的作用，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。这些研究还更加强调了胰岛素样生长因子结合蛋白-3的参与，这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的抑制剂。目前的研究考虑了对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殖反应的能力，以及糖尿病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了解，并将代表着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.