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

视网膜神经特异性 Bim 表达和发育中视网膜血管的高氧敏感性

• 批准号: 10299185
• 负责人: Ismail S Zaitoun
• 金额: $ 42.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299185
• 关键词: Adverse effects; Affect; Apoptosis; Apoptotic; Astrocytes; BCL2 gene; Blood Vessels; Blood capillaries; Cardiovascular system; Cell Death; Cells; Clinical; Complex; Development; Disease; Embryonic Development; Endothelial Cells; Exposure to; Eye diseases; Family member; Goals; Homeostasis; Hyperoxia; Ischemia; Knowledge; Mediating; Microglia; Modeling; Molecular; Mus; Myeloid Cells; Nerve Degeneration; Nerve Growth Factors; Neural Retina; Neuroglia; Neuronal Dysfunction; Neurons; Oxygen; Pathogenesis; Pathway interactions; Patients; Pericytes; Play; Pre-Clinical Model; Premature Infant; Process; Protein Family; Publishing; Regulation; Respiratory Insufficiency; Retina; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Source; Testing; Time; Vascular Endothelial Growth Factors; Vascular Proliferation; Vision; Work; angiogenesis; blood vessel development; effective therapy; insight; lung development; macroglia; member; mouse model; neovascularization; neuron apoptosis; neuron development; novel therapeutics; pre-clinical; prevent; pulmonary function; response; retina blood vessel structure; retinal angiogenesis; retinal apoptosis; retinal neuron; unpublished works; vascular contributions

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.

总结 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 在许多眼部疾病的进展中，包括早产儿视网膜病变（ROP）。因此了解 视网膜中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，Bcl-2蛋白家族的促凋亡成员Bim的整体缺失， 从高氧介导的血管闭塞和局部缺血介导的视网膜血管形成 ROP临床前小鼠模型中的新血管形成，氧诱导的缺血性视网膜病变（OIR） 模型此外，我们发现，在视网膜内皮细胞，周细胞或星形胶质细胞中，Bim的靶向缺失 不能保护发育中的视网膜血管系统免于暴露于高氧介导的血管闭塞，或 来自缺血介导的新血管形成。这些结果强烈支持Bim表达的重要作用 在视网膜内层神经元中，对视网膜血管系统的发育进行适当的调节。我们的假设是毕姆 在视网膜神经元中的表达在推导发育中的视网膜血管系统对 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形成。在Aim中 1，我们将确定Bim在视网膜内神经元中的表达对高氧诱导的血管内皮细胞凋亡的贡献。 损害在目标2中，我们将确定VEGF在视网膜内层神经元中的表达对视网膜神经元的作用。 高氧引起的血管损伤。了解视网膜神经元中的Bim表达如何调节视网膜神经元 血管发育和对高氧敏感性的增强将为Bim的作用机制提供深入了解 并有助于开发调节视网膜血管生成的替代方法。