Exsomes derived from retinal astrocytes in the regulation of retinal vasculature

 描述（由申请人提供）：正常的视网膜血管系统灌注神经感觉视网膜的黄斑，同时避免干扰图像分辨率。早产儿视网膜病变（ROP）、糖尿病视网膜病变（DR）、渗出性老年性黄斑变性（AMD）和血管闭塞中血管的异常生长和相关出血和/或血管渗漏是视力丧失的主要原因。多种细胞因子和可溶性因子参与了新生视网膜血管的形成、稳定和消退。在细胞成分中，视网膜星形胶质细胞（RACs）在原发性视网膜血管的内皮种植中起重要作用。然而，星形胶质细胞-内皮细胞相互作用的机制还不完全清楚。该提案研究了一种新的机制，其中RAC释放的外泌体靶向内皮细胞并导致正常的视网膜血管发育。为了检验我们的假设，即RAC外来体中的分子在正常视网膜血管系统的发育以及异常视网膜血管生成的抑制中是重要的，我们将1）测试来自鼠出生后第2天（P2）RAC的外来体的作用（开发RAC外来体）对使用视网膜内皮细胞的增殖、迁移和小管形成的影响; 2）确定正在发育的RAC外泌体是否可以挽救由低氧血症诱导的异常血管生成[即氧诱导的视网膜病变（OIR）];和3）确定这些外泌体的血管生成谱是否反映它们的功能。从这些结果中获得的信息将进一步我们理解RAC外泌体在正常视网膜血管系统的发育和维持中的作用。这些观察结果可能导致新的治疗，以控制异常视网膜血管生成。

 DESCRIPTION (provided by applicant): The normal retinal vasculature perfuses the macula of the neurosensory retina while avoiding interference with image resolution. The abnormal growth of blood vessels and associated bleeding and/or vascular leakage in retinopathy of prematurity (ROP), diabetics retinopathy (DR), exudative aged-related macular degeneration (AMD), and vascular occlusions are major causes of vision loss. Multiple cellular and soluble factors are involved in the formation, stabilization and regression of new retinal vessels. Among the cellular components, retinal astrocytes (RACs) play an important role in endothelial seeding of the primary retinal vasculature. However, the mechanism of astrocyte- endothelial cell interaction is incompletely understood. This proposal investigates a novel mechanism in which exosomes released by RACs target endothelial cells and result in normal retinal vasculature development. To test our hypothesis that molecules in RAC exosomes are important in the development of normal retinal vasculature, as well as the inhibition of aberrant retinal angiogenesis, we will 1) test the effect of exosomes from murine postnatal day 2 (P2) RACs (developing RAC exosomes) on proliferation, migration and tubule formation using retinal endothelial cells; 2) determine whether developing RAC exosomes can rescue aberrant angiogenesis induced by hypoxemia [i.e. oxygen-induced retinopathy (OIR)]; and 3) determine whether the angiogenic profiles of these exosomes reflect their function. Information derived from these results will further our understanding of the role of RAC exosomes in the development and maintenance of normal retinal vasculature. These observations may result in novel therapy to control aberrant retinal angiogenesis.