The Insulin-Like Growth Factor System and Muller Cells

描述（由申请人提供）：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 细胞疾病，因为它们是由单个细胞的活动引起的。 米勒细胞，视网膜的主要神经胶质细胞，在物理上与 糖尿病中的纤维收缩组织。此外，最近的研究表明， 米勒细胞能够产生牵引力， 胰岛素样生长因子I（IGF-1）刺激， 生物活性在糖尿病玻璃体中显著升高。因此 Muller细胞对IGF-1反应的研究与 增殖性糖尿病视网膜病变的发病机制。有趣的是， 糖尿病相关的玻璃体IGF-1活性增加不能用以下原因解释： 更高的生长因子浓度。IGF-1通常存在于 玻璃体在生物活性浓度，但生长因子活性 不能被检测到，这表明其他糖尿病相关的变化导致 IGF-1生物利用度增加或生长因子敏感性增强， 靶细胞据报告，这些类型的影响对 胰岛素样生长因子结合蛋白家族（IGFBPs）。符合 因此，IGFBPs的正常玻璃体补体在 糖尿病我们认为，糖尿病相关的玻璃体IGFBPs的变化， 比IGF-1是更高的生长因子活性的主要原因。 不幸的是，我们目前对IGFBP影响的理解并没有扩展到 Muller细胞或IGF-1诱导的纤维收缩过程。本申请 提出了五条调查路线来分析这种关系，包括 研究以确定（1）Muller细胞是否是玻璃体IGFBPs的来源， 糖尿病，（2）如果Muller细胞具有调节IGFBP活性的能力 通过分泌蛋白酶，（3）IGFBPs对IGF-1生物活性的影响 （4）如果IGFBPs具有直接生长， 对Muller细胞的因子非依赖性影响，和）5）如果Muller细胞活性 在糖尿病动物模型中得到支持。从这获得的信息 这项研究不仅将提高我们对纤维收缩过程的理解， 但应该代表着控制这种致盲的重大进展 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.