Inflammatory cytokines in diabetic retinopathy

糖尿病视网膜病变中的炎症细胞因子

• 批准号: 7096971
• 负责人: CHIARA GERHARDINGER
• 金额: $ 43.24万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096971
• 关键词: cell type; cytokine; diabetic retinopathy; receptor; retina

DESCRIPTION (provided by applicant): Diabetic retinopathy is the leading cause of blindness in the US adult population. To develop, effective approaches to prevent this disease, there is a crucial need for a better understanding of the mechanisms of diabetes-induced retinal damage. We have recently found that glial Muller cells mount an acute-phase response in diabetes, which is accompanied by retinal induction of the inflammatory cytokine interleukin 1¿ (IL-1¿). In this project, we intend to investigate the hypothesis that IL-1¿ upregulation contributes to the glial and vascular abnormalities of the diabetic retina. The specific aims are: 1. To identify the cell type/s that upregulate IL-1¿ and characterize the IL-1¿ system in the diabetic retina. The retinal cell type/s expressing IL-1¿ in diabetes will be identified by in situ hybridization and immunohistochemistry. To investigate the effect of diabetes on the IL-1¿ system, we will study the retinal expression and cellular distribution of the two IL-1¿ endogenous inhibitors - decoy receptor IL-1RII and receptor antagonist IL-1ra - and of the two components of the IL-1¿ signaling receptor - IL-1RI and IL-1RAcP. 2. To determine the mechanisms and consequences of IL-1¿ upregulation in retinal cells. We will perform in vitro studies to determine whether high glucose upregulates IL-1¿ in cell culture models. We will then investigate whether IL-1¿ is sufficient to mimic the effect of diabetes on Muller cells, and the interaction of IL-1¿ with other diabetes-induced factors. 3. To determine whether inhibition of IL-1¿ activity can prevent the development of diabetic retinopathy. As conclusive evidence for a role of IL-1¿ in diabetic retinopathy, we will evaluate the effect of retinal overexpression of IL-1ra in preventing retinal abnormalities in diabetic rats. Identifying IL-1¿ as a mediator of diabetes-induced retinal damage would open new avenues for the prevention of retinopathy. Recombinant IL-1ra or other anti-IL-1¿ drugs could become powerful tools to prevent retinopathy - with possible applications to other diabetic complications with an inflammatory component such as atherosclerosis.

描述（由申请人提供）：糖尿病视网膜病变是美国成年人失明的主要原因。为了开发有效的方法来预防这种疾病，迫切需要更好地了解糖尿病引起的视网膜损伤的机制。我们最近发现，神经胶质 Muller 细胞在糖尿病中产生急性期反应，并伴有视网膜诱导炎症细胞因子白细胞介素 1¿（IL-1¿）。在这个项目中，我们打算研究这样的假设：IL-1¿上调导致糖尿病视网膜的神经胶质和血管异常。具体目标是： 1. 鉴定上调 IL-1¿ 的细胞类型并表征糖尿病视网膜中的 IL-1 系统。糖尿病中表达IL-1的视网膜细胞类型将通过原位杂交和免疫组织化学来鉴定。为了研究糖尿病对 IL-1¿ 系统的影响，我们将研究两种 IL-1¿ 内源性抑制剂 - 诱饵受体 IL-1RII 和受体拮抗剂 IL-1ra - 以及 IL-1¿ 信号受体的两种成分 - IL-1RI 和 IL-1RAcP 的视网膜表达和细胞分布。 2. 确定视网膜细胞中IL-1¿上调的机制和后果。我们将进行体外研究，以确定高葡萄糖是否上调细胞培养模型中的 IL-1¿。然后我们将研究 IL-1¿ 是否足以模拟糖尿病对 Muller 细胞的影响，以及 IL-1 ¿ 与其他糖尿病诱导因素的相互作用。 3. 确定抑制IL-1¿活性是否可以预防糖尿病视网膜病变的发生。作为 IL-1 在糖尿病视网膜病变中作用的确凿证据，我们将评估视网膜过度表达 IL-1ra 在预防糖尿病大鼠视网膜异常中的作用。确定 IL-1 作为糖尿病引起的视网膜损伤的介质将为预防视网膜病变开辟新途径。重组IL-1ra或其他抗IL-1药物可能成为预防视网膜病变的有力工具，并可能应用于其他具有炎症成分的糖尿病并发症，例如动脉粥样硬化。