Influence of inflammatory mediators on RPE barrier function and choroidal neovascularization

炎症介质对RPE屏障功能及脉络膜新生血管的影响

• 批准号: 5434230
• 负责人: Professorin Dr. Antonia Joussen
• 金额: --
• 依托单位: Abteilung für Netzhaut- und Glaskörperchirurgie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2004
• 资助国家: 德国
• 起止时间: 2003-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5434230?language=en
• 关键词: Influence; inflammatory; mediators; RPE; barrier

Leukocytes have been implicated in the pathogenesis of AMD because their spatiotemporal distribution correlates with arborizing CNV in humans and in animal models. The proangiogenic growth factor VEGF induces the expression of intercellular adhesion molecule 1 (ICAM 1) on vascular endothelium and regulates leukocyte adhesion to endothelial cells. These systems are intertwined as leukocytes, which possess receptors for and migrate in response to VEGF, can also produce and release VEGF. It is currently believed that pathological angiogenesis is a manifestation of an imbalance between two growth factor families: the VEGF/Flt-1 system and the angiopoietin1, 2/Tie1,2 system. Ang-1 stabilizes vessels, whhereas Ang-2 promotes vascular remodeling in combination with VEGF and vessel regression in the absence of VEGF. The Fas-FasL system has been demonstrated to exert an inhibitory role by reducing endothelial sprouting. The discussion of a primary role of inflammation versus a secondary cause of choroidal neovascularization is stillnot solved, however there is evidence that the RPE cells via expression of pro- and anti-angiogenic molecules might play a central role. we use two transgenic mouse models to investigate whether the expression of those molecules within RPE cells is sufficient to regulate the angiogenic process that leads to choroidal neovascularization or whether ruptures of Bruch's membrane with or without inflammatory stimuli are prerequisite for the initiation of choroidal neovascularization. These experiments might shed light on the pathogenesis of choroidal neovascularization and help in the search for causal therapeutic strategies.

白细胞与AMD的发病机制有关，因为它们的时空分布与人类和动物模型中的树枝状CNV相关。促血管生成生长因子VEGF诱导血管内皮细胞表达细胞间粘附分子1（ICAM 1），调节白细胞与内皮细胞的粘附。这些系统交织在一起，因为白细胞具有VEGF受体并响应VEGF而迁移，也可以产生和释放VEGF。目前认为，病理性血管生成是两个生长因子家族之间失衡的表现：VEGF/Flt-1系统和血管生成素1，2/Tie 1，2系统。Ang-1稳定血管，而Ang-2与VEGF结合促进血管重塑，在VEGF缺乏的情况下促进血管消退。已证明Fas-FasL系统通过减少内皮发芽发挥抑制作用。炎症的主要作用与脉络膜新生血管的次要原因的讨论仍然没有解决，但是有证据表明，通过表达促血管生成和抗血管生成分子的RPE细胞可能发挥核心作用。我们使用两个转基因小鼠模型来研究RPE细胞内这些分子的表达是否足以调节导致脉络膜新生血管形成的血管生成过程，或者是否有或没有炎症刺激的布鲁赫膜破裂是脉络膜新生血管形成起始的先决条件。这些实验可能揭示脉络膜新生血管的发病机制，并有助于寻找因果关系的治疗策略。