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Interplay between AMPK and Hippo Signaling Regulates Ocular Antiviral Response to Zika virus infection

AMPK 和 Hippo 信号传导之间的相互作用调节眼部对寨卡病毒感染的抗病毒反应

基本信息

批准号：
10540701
负责人：
Vaithilingaraja Arumugaswami
金额：
$ 52.03万
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：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540701
关键词：
3-Dimensional 5&apos -AMP-activated protein kinase Ablation Address Affect Antiviral Response Atrophic Attenuated Biological Models Blood-Retinal Barrier Brain Diseases Cell Culture System Cell Density Cell Proliferation Cell physiology Cells Cessation of life Chemicals Cicatrix Code Cre lox recombination system Cytometry Cytoplasm Development Disease Progression Exhibits Eye Eye Abnormalities Eye Development Eye Injuries Eye diseases Fetal Development First Pregnancy Trimester Functional disorder Genes Genetic Histology Human Immune In Vitro Inflammatory Injury Innate Immune Response Interferon-beta Interferons Knock-out LATS1 gene Link Long-Term Effects Mediating Metabolic Metabolism Modeling Molecular Mus Ocular Pathology Organoids Outcome Measure Pathogenesis Pathogenicity Pathologic Pathway interactions Phosphorylation Phosphotransferases Physiological Pigments Predisposition Process Proteins RNA chemical synthesis Reflex action Regulation Reporting Resources Retina Retinal Diseases Role Second Pregnancy Trimester Series Signal Pathway Signal Transduction Stress Structure of retinal pigment epithelium TBK1 gene Teratogens Testing Tissues Tumor Suppressor Proteins Viral Viral Genome Virulence Factors Virus Virus Replication Vision Visual impairment ZIKA ZIKV disease ZIKV infection Zika Virus cell injury cell type conditioning design emerging human pathogen experimental study fetal fetal infection fundus imaging human pathogen in vivo Model induced pluripotent stem cell innate immune pathways insight knockout gene macula mouse model nervous system disorder novel organ growth pathogen pharmacologic primary outcome retinal progenitor cell sensor stem stem cells therapeutic target transmission process viral DNA

项目摘要

PROJECT SUMMARY: Zika virus (ZIKV) is a teratogenic human pathogen that causes congenital eye and brain diseases. Affected babies exhibit vision impairment and associated ocular pathology, including loss of foveal reflex and macular pigment mottling, chorioretinal scarring, and macular atrophy. ZIKV has become endemic and local transmissions in the USA have been reported previously. The long-term effects of structural damage on vision, as well as the pathogenic processes of congenital ZIKV eye diseases are beginning to be understood. The signaling pathways governing normal eye development, which are dysregulated during ZIKV infection, are not well characterized. We recently carried out a series of experiments by establishing a ZIKV infectious ocular cell culture system and mouse models to understand the structural and molecular perturbations. For successful replication, viruses have evolved various strategies to evade innate immune response as well as to enhance the availability of cellular metabolites required to meet the heightened energy demand for viral genome synthesis. We found that the AMPKα, a cellular master energy sensor, is activated in the ZIKV-infected retinal cells. Moreover, pharmacological activation of AMPK resulted in attenuated ZIKV replication. Another interesting finding is that the YAP/TAZ factors in the tumor suppressor Hippo/SWH signaling pathway were induced early on, but degraded at later stage of ZIKV infection in RPE cells. Silencing YAP/TAZ resulted in reduced ZIKV replication. Since the energy sensor AMPK and Hippo signaling pathways control key cellular processes, including host antiviral responses, it is critical to understand the fundamental mechanism of these two pathways deregulation. We hypothesize that ZIKV modulates AMPK and Hippo signaling pathways in ocular cells to 1) increase intracellular metabolic resources, and 2) inhibit TBK1 to antagonize antiviral defense. These molecular changes can be orchestrated through viral coded factors resulting in the pathogenesis of ocular cell injury. The following specific aims will be investigated. Aim 1 focuses on systematically evaluating the role of AMPK- Hippo signaling on regulating antiviral response to ZIKV infection in RPE cells. The cross talk between these pathways will be investigated at the YAP/TAZ level. Pharmacological activation/inhibition, and gene knockout approaches in RPE cells will be carried out. Aim 2 is designed to elucidate the effect of ZIKV on Hippo and AMPK signaling pathways during retinal development. Human iPSC-derived 3D-retinal cup organoids will be used to investigate the link between retinal development and ZIKV-mediated deregulation of these key pathways. The ZIKV-encoded virulence factors regulating these pathways will be characterized. Aim 3 is to determine the effect of RPE-specific ablation of AMPK, TBK1, and Hippo signaling on the pathogenesis of ZIKV-induced chorioretinal atrophy in mice. This proposed study would yield novel insights into the pathogenesis of ZIKV in ocular diseases and identification of potential therapeutic targets.

寨卡病毒（ZIKV）是一种致畸的人类病原体，可导致先天性眼睛和大脑