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

基本信息

批准号：
10673013
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
项目类别：
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/10673013
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 Induction of Apoptosis 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 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prevent pulmonary function response retina blood vessel structure retinal angiogenesis retinal apoptosis retinal neuron unpublished works vascular contributions

项目摘要

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.

概括血管生成是胚胎循环系统正常发育所必需的，是一个重要的步骤许多眼部疾病的进展，包括早产儿视网膜病变 (ROP)，因此需要了解。视网膜中的正常调节机制如何控制血管生成具有重大的临床意义。我们最近发现 Bim（Bcl-2 蛋白家族的促凋亡成员）的整体缺失可以保护通过高氧介导的血管闭塞和缺血介导的视网膜血管系统的发育 ROP（氧诱导缺血性视网膜病变 (OIR)）临床前小鼠模型中的新生血管形成此外，我们还发现视网膜内皮细胞、周细胞或星形胶质细胞中的 Bim 被靶向删除。不能保护视网膜脉管系统免受高氧介导的血管闭塞或这些结果有力地支持了 Bim 表达的重要作用。我们的假设是，Bim 在视网膜内部神经元中对发育中的视网膜脉管系统进行适当调节。视网膜神经元中的表达在产生发育中的视网膜脉管系统对 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。 1，我们将确定视网膜内神经元中Bim表达对高氧诱导的血管损伤的贡献在目标 2 中，我们将确定视网膜内神经元中 VEGF 表达对损伤的贡献。了解高氧诱导的血管损伤。视网膜神经元中的 Bim 表达如何调节视网膜。血管发育和对高氧敏感性的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。