Role of ABCG1 in Zika virus induced chorioretinal atrophy

ABCG1 在寨卡病毒诱导的脉络膜视网膜萎缩中的作用

• 批准号: 9436896
• 负责人: Ashok Kumar
• 金额: $ 19.25万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9436896
• 关键词: Ablation; Acute; Address; Adult; Animals; Antiviral Agents; Antiviral Response; Atrophic; Attenuated; Binding; Biological Process; Blood-Borne Pathogens; Blood-Retinal Barrier; Brazil; CASP3 gene; Candidate Disease Gene; Cell Death; Cells; Ceramides; Cholesterol; Cholesterol Homeostasis; Chorioretinitis; Clinical; Clinical Research; Congenital Disorders; Consequentialism; Data; Databases; Dengue; Disease; Disease Outbreaks; Ear; Event; Eye; Family; Fatty Acids; Flavivirus; Functional disorder; Gene Silencing; Genes; Goals; Health; Hepatitis C; Histology; Human; Immune response; In Situ Nick-End Labeling; In Vitro; Infant; Infection; Inflammatory Response; Innate Immune Response; Integration Host Factors; Interferons; International; Japanese Encephalitis; Knock-out; Laboratories; Lesion; Limb structure; Link; Membrane Transport Proteins; Meta-Analysis; Metabolism; Microcephaly; Molecular; Mus; Neurologic Symptoms; Neurons; Ocular Pathology; Ontology; Organ; Outcome; Pathogenesis; Pathologic; Pathology; Pharmacology; Pregnancy; Prevention; Production; Property; Reporting; Retina; Retinal; Retinal Diseases; Role; SRE-2 binding protein; Secondary to; Structure of retinal pigment epithelium; Supplementation; Systems Biology; Testing; Therapeutic; Tissues; Uveitis; Validation; Vascular Endothelium; Viral load measurement; Virus; Virus Replication; Visual; West Nile virus; Work; ZIKV infection; Zika Virus; base; cell type; chemokine; cholesterol biosynthesis; cholesterol transporters; cytokine; design; disorder of macula of retina; drug development; fundus imaging; global health; in vivo; insight; interest; lipid biosynthesis; lipid metabolism; lipid transport; macrophage; macula; member; microbial; mouse model; nervous system disorder; pathogen; prevent; public health emergency; receptor; recombinase-mediated cassette exchange; response; retinal damage; transcriptome; transcriptome sequencing; virus pathogenesis

Project Summary The most recent outbreak of Zika Virus (ZIKV) in Brazil has presented with unexpectedly severe neurological manifestations, which were not observed in prior outbreaks of ZIKV or other related flaviviruses. This prompted the WHO to declare a public health emergency of international In addition to neurologic disorders, ZIKV infection is now being increasingly associated with ocular complications such as uveitis, acute maculopathy, pigmentory retinopathy, and chorioretinal atrophy. These clinical findings make it clear that macular and chorioretinal disease can significantly impact visual outcomes in ZIKV-infected infants and adults. However, it is not yet clear whether congenital ocular complications are directly caused by ZIKV or are secondary to microcephaly. As the retina is the primary target of ZIKV in the eye, we have developed a mouse model of ZIKV-induced chorioretinal atrophy. We found that cells lining the blood-retinal barrier (BRB), the retinal pigment epithelium (RPE), are highly permissive to ZIKV. Collectively, these findings led us to postulate that ZIKV gains access to the eye by via BRB. Despite the close relationship between ZIKV and other members of the flaviviridae family, such as DENV, WNV, and JEV, it remains unclear why only ZIKV causes congenital disorders and associated complications. To address this question , we compared the transcriptome of ZIKV-infected RPE cells with the transcriptome signatures of the other related viruses. This led to the identification of ABCG1, a cholesterol membrane transporter, as a candidate gene that is specifically involved in the pathogenesis of ZIKV. In support, our preliminary data show that pharmacological inhibition of ABCG1 activity attenuated ZIKV replication in RPE cells. Thus, the overall objective of this study concern. is to determine molecular mechanisms by which ABCG1 promotes viral replication in RPE and determine the consequences of ABCG1 ablation in the pathobiology of ZIKV-induced chorioretinal atrophy. To achieve this goal, we will pursue two specific aims: Aim-1 is to determine how ZIKV-induced ABCG1 expression modulates cholesterol synthesis/efflux to promote ZIKV replication in RPE cells. Aim-2 is designed to investigate the role of ABCG1 in the pathobiology of ZIKV-induced chorioretinal atrophy in ABCG1-BEST1Cre mice harboring an RPE-specific conditional knockout. Upon completion, these aims will elucidate the role of ABCG1 in ocular ZIKV infection, particularly in the pathogenesis of chorioretinal atrophy. Given the rapid spread of ZIKV and its impact on ocular health, this work is of paramount importance for the development of drugs to treat ZIKV infection and prevent its complications.

项目摘要 寨卡病毒（ZIKV）在巴西的最新爆发已经呈现出意想不到的严重 神经系统表现，这在ZIKV或其他相关疾病的先前爆发中没有观察到。 黄病毒这促使世界卫生组织宣布国际公共卫生紧急状态 除了神经系统疾病，ZIKV感染现在越来越多地被 与眼部并发症如葡萄膜炎、急性黄斑病变、色素沉着 视网膜病和脉络膜视网膜萎缩。这些临床发现清楚地表明，黄斑和 脉络膜视网膜疾病可显著影响ZIKV感染婴儿的视力结果， 成年人了但目前尚不清楚先天性眼部并发症是否直接引起 或继发于小头畸形。由于视网膜是ZIKV在视网膜病变中的主要靶点， 眼，我们已经开发了ZIKV诱导的脉络膜视网膜萎缩的小鼠模型。我们发现 内衬血视网膜屏障（BRB）的细胞，即视网膜色素上皮（RPE），高度 允许ZIKV。总的来说，这些发现使我们假设ZIKV获得了 通过BRB的眼睛。尽管ZIKV和其他成员之间的密切关系， 尽管ZIKV是黄病毒科家族的成员，例如DENV、WNV和JEV，但仍然不清楚为什么只有ZIKV引起 先天性疾病和相关并发症。为了解决这个问题，我们比较了 ZIKV感染的RPE细胞的转录组与另一个细胞的转录组特征 相关病毒这导致了ABCG 1的鉴定，ABCG 1是一种胆固醇膜转运蛋白， 作为特异性参与ZIKV发病机制的候选基因。为了支持，我们的 初步数据显示ABCG 1活性的药理学抑制减弱了ZIKV 在RPE细胞中复制。因此，本研究的总体目标 关心 是确定分子 ABCG 1促进RPE中病毒复制的机制，并决定了 ABCG 1消融在ZIKV诱导的脉络膜视网膜萎缩的病理生物学中的后果。到 为了实现这一目标，我们将追求两个具体目标：目标-1是确定ZIKV如何诱导 ABCG 1表达调节胆固醇合成/流出以促进RPE中的ZIKV复制 细胞目的-2旨在研究ABCG 1在ZIKV诱导的肿瘤病理学中的作用。 携带RPE特异性条件性敲除的ABCG 1-BEST 1Cre小鼠中的脉络膜视网膜萎缩。 完成后，这些目标将阐明ABCG 1在眼部ZIKV感染中的作用， 特别是在脉络膜视网膜萎缩的发病机制中。鉴于ZIKV的快速传播及其 影响眼部健康，这项工作对于药物的开发至关重要， 治疗ZIKV感染并预防其并发症。