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最终是 细胞疾病是由单个细胞的活动引起的。 穆勒细胞，视网膜的主要神经胶质细胞，在物理上与 糖尿病患者的纤维收缩组织。此外，最近的研究表明， 穆勒细胞能够产生牵引力，这种活动 是由胰岛素样生长因子I(IGF-1)刺激的，IGF-1是一种生长因子，其 糖尿病患者的玻璃体生物活性显著升高。因此， 研究MULER细胞对IGF-1的反应与 增殖性糖尿病视网膜病变的发病机制。有趣的是， 糖尿病引起的玻璃体IGF-1活性升高不能用 单单是更高的生长因子浓度。IGF-1通常存在于 玻璃体的生物活性浓度，但生长因子活性 无法检测到，这表明其他与糖尿病相关的变化会导致 IGF-1生物利用度增加或生长因子敏感性增强 目标单元格。这些类型的影响已被报告为 胰岛素样生长因子结合蛋白家族(IGFBPs)。与一致 这一点，IGFBPs的正常玻璃体补充在 糖尿病。我们认为糖尿病引起的玻璃体内IGFBPs的改变 高于IGF-1是生长因子活性较高的主要原因。 不幸的是，我们目前对IGFBP效应的理解还没有扩展到 Muller细胞或IGF-1诱导的纤维收缩过程。此应用程序 提出了分析这种关系的五条调查路线，包括 研究确定(1)Muller细胞是否是玻璃体IGFBPs的来源 糖尿病，(2)穆勒细胞是否具有调节IGFBP活性的能力 (3)IGFBPs对IGF-1生物效应的影响 相对于Muller细胞的活性，(4)如果IGFBPs有直接的，生长 对米勒细胞的非因素影响和)5)如果穆勒细胞活动 在糖尿病动物模型中得到支持。从这个过程中获得的信息 研究不仅将提高我们对纤维收缩过程的理解， 但这应该代表着在控制这种致盲方面取得了重大进展 糖尿病视网膜病变的并发症。

DESCRIPTION (provided by applicant): 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.