Role of Zika virus (ZIKV) infection in glaucoma pathobiology

寨卡病毒（ZIKV）感染在青光眼病理学中的作用

• 批准号: 10474371
• 负责人: Pawan kumar Singh
• 金额: $ 36.46万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474371
• 关键词: Acids; Affect; Animal Model; Anterior; Anterior eyeball segment structure; Antibodies; Antibody-Dependent Enhancement; Antiviral Response; Atrophic; Autophagocytosis; Axonal Transport; Case Study; Cell Death; Cell model; Cells; Cessation of life; Choroid; Clinical; Country; Development; Disease; Epidemic; Exhibits; Experimental Models; Exposure to; Extracellular Matrix; Eye; FDA approved; Flavivirus; Flavivirus Infections; Functional disorder; Future; Genetic; Glaucoma; Goals; Human; Hydrophthalmos; Hydroxychloroquine; Hypoxia; IFNAR1 gene; In Vitro; Infant; Infection; Knock-out; Laboratories; Link; Mediating; Microcephaly; Modeling; Molecular; Mothers; Mus; Neonatal; Newborn Infant; Optic Nerve; Outcome Study; Pathogenesis; Pathologic; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacology; Physiologic Intraocular Pressure; Pigmentation physiologic function; Pigments; Posterior eyeball segment structure; Pregnancy; Prevention; Publishing; Reporting; Retina; Retinal Ganglion Cells; Role; Sirolimus; Stimulus; Testing; Therapeutic; Time; Tissues; Trabecular meshwork structure; Treatment Efficacy; Virus Replication; Visual; ZIKV infection; Zika Virus; age related; anterior chamber; aqueous; attenuation; base; biological adaptation to stress; combat; congenital infection; congenital zika syndrome; endoplasmic reticulum stress; global health; in vivo; in vivo Model; inhibition of autophagy; inhibitor; interferon alpha receptor; intraperitoneal; macula; mouse model; neonate; nerve damage; novel; novel therapeutics; offspring; pathogenic virus; prevent; primary outcome; prognostic; pup; retina blood vessel structure; therapeutic target; tool; transcriptome sequencing; transcriptomics; transmission process; type I interferon receptor

PROJECT SUMMARY The overall goal of this project is to investigate the role of Zika virus (ZIKV) in glaucoma pathobiology. ZIKV is an emerging viral pathogen that causes microcephaly and leads to severe ocular complications in newborns born to ZIKV infected mothers. Although the ocular manifestations of ZIKV are primarily reported to affect the posterior segment of the eye resulting in chorioretinal atrophy, withering of the retina and choroid, and optic nerve abnormalities, several clinical case reports showed the involvement of the anterior segment resulting in glaucoma. Studies from our laboratory, as well as those of others, have shown that ZIKV can cause glaucomatous pathology including an increase in intraocular pressure (IOP), retinal ganglion cell (RGC) loss, and optic nerve damage. The offspring of ZIKV infected dams have shown increased IOP and RGC loss and the presence of anti-flavivirus-antibody in these mice correlates with significantly enhanced glaucoma pathology due to antibody-dependent enhancement. Until the recent ZIKV epidemics, glaucoma has been primarily considered as a genetic and age-related disease and has not been reported among infants exposed to infection during gestation. Several studies have now reported that ZIKV can cause congenital glaucoma in infants born from mothers who were infected during pregnancy. Considering the fact that there is an endemic transmission of ZIKV in >84 countries, it is imperative to investigate the link between ZIKV and glaucoma to develop new prognostic and therapeutic tools to combat this global health threat. Our laboratory has developed several in vitro and in vivo models to study the pathobiology of ocular ZIKV infections. In our recent study, we reported that ZIKV can infect and replicate in human primary Trabecular Meshwork cells (HTMC). More recently, we performed RNAseq analysis and discovered that ZIKV infection of HTMC leads to transcriptomic alteration and dysregulation of several pathways including those that modulate ER stress response, autophagy, hypoxia, and ECM organization. Furthermore, ZIKV-infected mice exhibited increased IOP, ER stress, and autophagy in the anterior segment of the eye. ZIKV infection also caused RGC death and loss of RGC and optic nerve damage leading to disruption of anterograde axonal transport. Based on these novel findings, we hypothesize that ZIKV induces ER stress and autophagy resulting in TM death and dysfunction, increased IOP, and the development of glaucoma. Two specific aims are proposed to test this hypothesis. Aim 1 will determine the role of ZIKV induced ER stress in TM dysfunction and the pathobiology of glaucoma using C57BL/6 (WT) and IFNAR1-/- mice/pups and whether the reduction of ER stress alleviates ZIKV induced glaucomatous pathology. Aim 2 will investigate the role of autophagy using HTMC, and mouse models and evaluate the therapeutic efficacy of an FDA approved drug, hydroxychloroquine (HCQ) in ZIKV induced glaucoma. The anticipated results will establish the role of ZIKV infection in the pathogenesis of glaucoma and elucidate the molecular mechanisms and pathway-mediated therapeutic targets for future treatments.

项目摘要 该项目的总体目标是研究寨卡病毒（ZIKV）在青光眼病理学中的作用。ZIKV是 一种新出现的病毒病原体，可导致新生儿小头畸形和严重的眼部并发症 ZIKV感染的母亲。虽然ZIKV的眼部表现主要被报道影响患者的视力。 眼后段导致脉络膜视网膜萎缩、视网膜和脉络膜萎缩，以及视神经萎缩。 神经异常，几个临床病例报告显示累及眼前节导致 青光眼我们实验室的研究以及其他人的研究表明，ZIKV可以导致 青光眼病理学包括眼内压（IOP）升高，视网膜神经节细胞（RGC）丢失， 和视神经损伤。ZIKV感染的母鼠的后代显示出增加的IOP和RGC损失， 这些小鼠中抗黄病毒抗体存在与显著增强的青光眼相关 病理学由于抗体依赖性增强。直到最近的ZIKV流行病，青光眼一直是 主要被认为是一种遗传性和年龄相关疾病，尚未报告接触该疾病的婴儿 怀孕期间的感染。现在有几项研究报告说，ZIKV可以导致先天性青光眼， 母亲在怀孕期间感染艾滋病毒所生的婴儿。考虑到有一种地方性的 由于ZIKV在>84个国家传播，因此必须调查ZIKV与青光眼之间的联系， 开发新的预后和治疗工具，以应对这一全球健康威胁。我们的实验室开发了 本发明涉及几种体外和体内模型以研究眼部ZIKV感染的病理生物学。在最近的研究中，我们 ZIKV可以感染人原代小梁网细胞（HTMC）并在其中复制。更 最近，我们进行了RNAseq分析，发现HTMC的ZIKV感染导致转录组学改变， 改变和失调的几个途径，包括那些调节ER应激反应， 自噬缺氧和ECM组织此外，ZIKV感染的小鼠表现出增加的IOP、ER 压力和眼前段的自噬。ZIKV感染还导致RGC死亡和细胞凋亡。 RGC和视神经损伤导致顺行轴突运输中断。根据这些小说 研究结果，我们假设ZIKV诱导ER应激和自噬，导致TM死亡和功能障碍， 眼压升高和青光眼的发展。提出了两个具体目标来检验这一假设。目的 1将确定ZIKV诱导的ER应激在TM功能障碍和青光眼病理生物学中的作用， C57 BL/6（WT）和IFNAR 1-/-小鼠/幼仔以及ER应激的减少是否破坏ZIKV诱导的 青光眼病理学。目的2将使用HTMC和小鼠模型研究自噬的作用， 评估FDA批准的药物羟氯喹（HCQ）在ZIKV诱导的ZIKV中的治疗功效。 青光眼预期的结果将确立ZIKV感染在青光眼发病机制中的作用， 阐明未来治疗的分子机制和途径介导的治疗靶点。