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

点击翻译按钮获取中文摘要

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.