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 巴西最新的寨卡病毒（ZIKV）爆发出人意料地出现了严重 神经表现形式，在ZIKV或其他相关的先前暴发中未观察到这些表现 黄病毒。这促使世卫组织宣布国际公共卫生紧急 除了神经系统疾病外，ZIKV感染现在越来越多 与眼部并发症，例如葡萄膜炎，急性颗粒病，色素 视网膜病和脉络化萎缩。这些临床发现清楚地表明了黄斑和 脉络膜视网膜疾病会显着影响ZIKV感染的婴儿和 成年人。但是，尚不清楚先天性眼并发症是否直接引起 由ZIKV或继发于小头畸形。因为视网膜是ZIKV的主要目标 眼睛，我们开发了ZIKV诱导的脉络膜视网膜萎缩的小鼠模型。我们发现 血液 - 视网膜屏障（BRB），视网膜色素上皮（RPE）的细胞高度 允许Zikv。总的来说，这些发现使我们假设Zikv可以访问 通过BRB的眼睛。尽管Zikv与其他成员之间有着密切的关系 Flaviviridae家族，例如DENV，WNV和JEV，尚不清楚为什么仅ZIKV造成 先天性疾病和相关并发症。为了解决这个问题，我们将 ZIKV感染的RPE细胞的转录组，具有另一个的转录组特征 相关病毒。这导致了ABCG1的鉴定，ABCG1是胆固醇膜转运蛋白， 作为特别参与ZIKV发病机理的候选基因。支持我们 初步数据表明，ABCG1活性的药理抑制减弱了ZIKV RPE细胞中的复制。因此，这项研究的总体目标 忧虑。 是确定分子 ABCG1在RPE中促进病毒复制的机制并确定 ABCG1消融在ZIKV诱导的脉络化视网膜萎缩的病理生物学中的后果。到 实现这一目标，我们将追求两个具体的目标：AIM-1是确定ZIKV诱导的 ABCG1表达调节胆固醇的合成/外排以促进RPE中的ZIKV复制 细胞。 AIM-2旨在研究ABCG1在ZIKV诱导的病理生物学中的作用 ABCG1-BEST1CRE小鼠中的脉络化视网膜萎缩，具有特定于RPE的条件敲除。 完成后，这些目标将阐明ABCG1在眼部ZIKV感染中的作用， 特别是在脉络化萎缩的发病机理中。考虑到Zikv及其迅速传播 对眼部健康的影响，这项工作对于开发药物至关重要 治疗ZIKV感染并防止其并发症。