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

基本信息

批准号：
10624426
负责人：
Alison Chu
金额：
$ 39.16万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624426
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 Epithelium 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 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 comparison control differential expression extreme prematurity 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

项目摘要

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.

项目摘要早产视网膜病（ROP）是儿童失明的主要原因，影响3-4中的1个出生体重的早产婴儿。早产需要将这些新生儿暴露于相对高氧由于其肺不成熟。高氧导致视网膜的血管衰减，从而导致局部缺氧，然后燃烧异常的补偿性新血管形成（NV）。这个过程是由生长因子的表达改变，例如血管内皮生长因子（VEGF）。虽然神经素已经描述为在ROP中的促血管生成信号传导中发挥作用，这些机制仍然很少理解。 ROP的当前疗法治疗晚期永久性新生血管形成，并未解决神经网络功能障碍 ROP。在这笔赠款中，我们建议了解VEGF上皮膜的上游调节器的作用蛋白-2（EMP2），在视网膜病变的氧诱导的鼠模型中。 EMP2，一种对细胞到细胞信号很重要的四叠酸酯膜蛋白，通过VEGF和缺氧诱导因子（HIF）1α调节，在某些癌症和斑点疾病中。我们假设这一点 EMP2也是眼睛中缺氧介导的病理新血管生成的调节剂。我们的来自氧诱导的视网膜病（OIR）的小鼠模型的初步数据证明了遗传敲除 EMP2的抑制作用会减弱NV并抑制神经素中的HIF1α和VEGFA表达。而且，OIR 在生理状态下的神经素中诱导EMP2表达，在神经素中表达较低和RPE和角膜中的高表达。但是，EMP2表达的作用及其在发展神经素是未知的。该提案的目标是确定临时和空间 EMP2在正常残留发育以及OIR病理条件下的表达和功能。那，我们试图了解EMP2调节神经视网膜血管生成信号的机制。我们假设EMP2表达通常分离为成年小鼠的视网膜色素上皮（RPE）视网膜在发育中的眼睛中的神经视网膜细胞中增加（AIM 1），在那里它直接调节了HIF- 从这些细胞中介导的VEGF产生（AIM 2）。我们进一步假设抗体介导的靶向 EMP2将安全有效地衰减病理NV（AIM 3）。我们的方法是多学科的，具有新生儿新生儿/血管疾病专家，EMP2生物学，视网膜疾病，基因组学和高级成像。我们将利用生化，物理，基因组和体内的光学成像方法评估EMP2表达，功能和下游血管生成效应。这项研究的中心创新是：（1）进一步了解神经素在氧气中的作用通过EMP2介导的血管生成因子产生引起的视网膜病变，（2）应用知识 EMP2通过VEGF表达在癌症，放置和成人眼病中对血管生成的影响。