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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：
10404080
负责人：
Alison Chu
金额：
$ 37.99万
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/10404080
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

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.

项目总结