Neural Retina-Specific Bim Expression and Hyperoxia Sensitivity of the Developing Retinal Vasculature

摘要 血管生成是胚胎循环系统正常发育所必需的，也是重要的一步。 在许多眼科疾病的进展中，包括早产儿视网膜病变(ROP)。因此，理解 视网膜的正常调节机制如何控制血管生成具有重要的临床意义。 我们最近发现了Bim的全球缺失，Bim是一种促凋亡的蛋白质家族成员，可以保护 高氧介导的血管闭塞和缺血介导的视网膜血管形成 临床前ROP小鼠氧诱导的视网膜缺血性病变模型中新生血管的形成 模特。此外，我们发现，在视网膜内皮细胞、周细胞或星形胶质细胞中靶向删除Bim 不能保护发育中的视网膜血管免受高氧介导的血管闭塞或 来自缺血介导的新生血管。这些结果有力地支持了BIM表达的重要作用 在视网膜内神经元中适当调节发育中的视网膜血管系统。我们的假设是比姆 视网膜神经元的表达在视网膜血管发育对 ROP期间高氧介导的血管闭塞和缺血介导的视网膜新生血管。在AIM 1，我们将确定Bim在视网膜内神经元表达在高氧诱导血管形成中的作用。 损坏。在目标2中，我们将确定视网膜内神经元中血管内皮生长因子的表达对 高氧引起的血管损伤。了解视网膜神经元中Bim的表达如何调节视网膜 血管发育和对高氧的敏感性增强将有助于深入了解BIM的作用机制 并帮助开发调节视网膜血管生成的替代方法。

Summary Angiogenesis is required for proper development of the embryonic circulatory system and is an important step in the progression of many eye diseases, including retinopathy of prematurity (ROP). Therefore, understanding how the normal regulatory mechanisms in the retina keep angiogenesis in check has great clinical implications. We recently showed global deletion of Bim, a proapoptotic member of Bcl-2 family of proteins, protects the developing retinal vasculature from hyperoxia–mediated vessel obliteration and ischemia-mediated neovascularization in the preclinical mouse model of ROP, the oxygen-induced ischemia retinopathy (OIR) model. In addition, we showed that targeted deletion of Bim in retinal endothelial cells, pericytes or astrocytes does not protect the developing retinal vasculature from exposure to hyperoxia–mediated vessel obliteration or from ischemia-mediated neovascularization. These results strongly support an important role for Bim expression in retinal inner neurons in proper regulation of developing retinal vasculature. Our hypothesis is that Bim expression in retinal neurons plays a central role in deriving the sensitivity of developing retinal vasculature to hyperoxia–mediated vessel obliteration and ischemia–mediated retinal neovascularization during ROP. In Aim 1, we will determine the contribution of Bim expression in the inner retinal neurons to hyperoxia-induced vascular damage. In Aim 2, we will determine the contribution of VEGF expression in the inner retinal neurons to hyperoxia-induced vascular damage. Understanding how Bim expression in retinal neurons regulates retinal vascular development and enhanced sensitivity to hyperoxia will provide insight into Bim mechanisms of action and aid in the development of alternative ways to modulate retinal angiogenesis.