Targeting epithelial membrane protein 2 (EMP2) in retinopathy of prematurity

靶向上皮膜蛋白 2 (EMP2) 治疗早产儿视网膜病变

• 批准号: 10183025
• 负责人: Alison Chu
• 金额: $ 40.56万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10183025
• 关键词: 3-Dimensional; Adult; Affect; Angiogenic Factor; Antibodies; Attenuated; Biochemical; Biology; Blindness; Blood Vessels; Cells; Childhood; Cornea; Data; Defect; Development; Disease; Disease Progression; Endothelium; Environment; Epithelial; Exhibits; Extremely Low Birth Weight Infant; Eye; Eye diseases; Foundations; Functional disorder; Genetic; Genomics; Goals; Grant; Growth Factor; HIF1A gene; Histologic; Hyperoxia; Hypoxia; Hypoxia Inducible Factor; Image; Infant; Kidney; Knock-out; Knockout Mice; Knowledge; Light; Link; Lung; Malignant Neoplasms; Measures; Mediating; Membrane Proteins; Modeling; Mus; National Eye Institute; Neonatology; Neurodevelopmental Disability; Neurons; Oxygen; Pathogenicity; Pathologic; Pathologic Neovascularization; Pattern; Phase; Photoreceptors; Physiological; Placenta Diseases; Placentation; Play; Population; Premature Birth; Premature Infant; Process; Production; Research; Retina; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Rod; Role; Safety; Signal Transduction; Structure; Structure of retinal pigment epithelium; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; VEGFA gene; Vascular Diseases; Vascular Endothelial Growth Factors; Vascularization; Visual; angiogenesis; attenuation; blood vessel development; differential expression; hypoxia inducible factor 1; imaging modality; in vivo; innovation; interdisciplinary approach; intravitreal injection; mouse model; multidisciplinary; neonate; neovascularization; new therapeutic target; novel; optical imaging; prevent; retina blood vessel structure; retinal angiogenesis; selective expression; single-cell RNA sequencing; therapeutic evaluation; transcriptomics; vasculogenesis

PROJECT SUMMARY Retinopathy of prematurity (ROP) is a leading cause of childhood blindness, affecting approximately 1 in 3-4 extremely low birth weight premature infants. Preterm delivery requires exposing these neonates to relative hyperoxia because of their lung immaturity. Hyperoxia leads to vessel attenuation in the retina, which results in local hypoxia, which then fuels abnormal compensatory neovascularization (NV). This process is mediated by altered expression of growth factors such as vascular endothelial growth factor (VEGF). Though the neuroretina has been described to play a role in pro-angiogenic signaling in ROP, the mechanisms remain poorly understood. Current therapies for ROP treat late retinal neovascularization and do not address neuroretinal dysfunction in ROP. In this grant, we propose to understand the role of an upstream regulator of VEGF, epithelial membrane protein-2 (EMP2), in an oxygen-induced murine model of retinopathy. EMP2, a tetraspanin membrane protein important for cell-to-cell signaling, regulates angiogenesis via VEGF and hypoxia inducible factor (HIF)1α modulation in select cancers and placental diseases. We hypothesize that EMP2 serves as a regulator of hypoxia-mediated pathological neoangiogenesis in the eye as well. Our preliminary data from a mouse model of oxygen-induced retinopathy (OIR) demonstrates that genetic knock out of EMP2 attenuates NV and suppresses HIF1α and VEGFA expression in the neuroretina. Moreover, OIR induces EMP2 expression in the neuroretina, which in physiologic states, has low expression in the neuroretina and high expression in the RPE and cornea. However, the role for EMP2 expression and its function in the developing neuroretina is unknown. The goals of this proposal are to determine the temporal and spatial expression and function of EMP2 in normal retinal development as well as in pathologic conditions of OIR. Thus, we seek to understand the mechanisms by which EMP2 regulates neuroretinal angiogenic signaling. We hypothesize that EMP2 expression, normally isolated to the retinal pigment epithelium (RPE) in the adult mouse retina, is increased in neuroretinal cells in OIR in the developing eye (Aim 1), where it directly regulates HIF- mediated VEGF production from these cells (Aim 2). We further hypothesize that antibody-mediated targeting of EMP2 will safely and effectively attenuate pathologic NV (Aim 3). Our approach is multidisciplinary, with experts in neonatology/vascular disease in neonates, EMP2 biology, retinal diseases, genomics, and advanced imaging. We will utilize biochemical, physiological, genomic, and optical imaging methods in vivo to assess EMP2 expression, function, and the downstream angiogenic effect. The central innovations of this study are to: (1) further our understanding of the neuroretina’s role in oxygen- induced retinopathy via EMP2-mediated angiogenic growth factor production, and (2) apply the knowledge of EMP2’s effects on angiogenesis via VEGF expression in cancer, placentation, and adult eye disease to ROP.

项目概要 早产儿视网膜病变 (ROP) 是儿童失明的主要原因，影响大约三到四分之一的儿童 出生体重极低的早产儿需要让这些新生儿接触亲属。 由于肺部不成熟而导致高氧血症，导致视网膜血管衰减。 局部缺氧，进而促进异常代偿性新生血管形成（NV）。 改变神经视网膜等生长因子的表达。 已被描述在 ROP 的促血管生成信号传导中发挥作用，但其机制仍知之甚少。 目前的 ROP 疗法只能治疗晚期视网膜新生血管形成，不能解决神经视网膜功能障碍问题。 ROP。在这项资助中，我们建议了解 VEGF 的上游调节剂（上皮膜）的作用。 Protein-2 (EMP2)，在氧诱导的小鼠视网膜病变模型中。 EMP2 是一种对细胞间信号转导很重要的四跨膜蛋白，通过 VEGF 调节血管生成， 缺氧诱导因子 (HIF)1α 对某些癌症和胎盘疾病的调节。 EMP2 也是眼部缺氧介导的病理性新生血管生成的调节剂。 氧诱导视网膜病变 (OIR) 小鼠模型的初步数据表明，基因敲除 EMP2 可以减弱 NV 并抑制神经视网膜中 HIF1α 和 VEGFA 的表达。 诱导神经视网膜中 EMP2 的表达，在生理状态下，EMP2 在神经视网膜中表达较低 然而，EMP2 表达的作用及其在 RPE 和角膜中的功能。 发育中的神经视网膜尚不清楚，该提案的目标是确定时间和空间。 EMP2 在正常视网膜发育以及 OIR 病理条件下的表达和功能。 我们试图了解 EMP2 调节神经视网膜血管生成信号传导的机制。 最近发现 EMP2 表达通常分离于成年小鼠的视网膜色素上皮 (RPE) 视网膜，在发育中的眼睛中 OIR 中的神经视网膜细胞增加（目标 1），它直接调节 HIF- 介导这些细胞产生 VEGF（目标 2）。 EMP2 将安全有效地减弱病理性 NV（目标 3）。 我们的方法是多学科的，拥有新生儿学/新生儿血管疾病、EMP2 生物学、 我们将利用生物化学、生理学、基因组学和视网膜疾病、基因组学和先进成像技术。 体内光学成像方法评估 EMP2 表达、功能和下游血管生成效应。 这项研究的核心创新点是：（1）进一步了解神经视网膜在氧气中的作用 通过 EMP2 介导的血管生成生长因子的产生诱导视网膜病变，以及 (2) 应用以下知识 EMP2 通过 VEGF 表达对癌症、胎盘形成和成人眼病至 ROP 中的血管生成产生影响。