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

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

项目成果

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Vaithilingaraja Arumugaswami其他文献

Vaithilingaraja Arumugaswami的其他文献

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{{ truncateString('Vaithilingaraja Arumugaswami', 18)}}的其他基金

Metabolic and epigenetic reprogramming of vital organs in SARS-CoV-2 induced systemic toxicity
SARS-CoV-2 引起的全身毒性中重要器官的代谢和表观遗传重编程
  • 批准号:
    10272660
  • 财政年份:
    2021
  • 资助金额:
    $ 50.47万
  • 项目类别:
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
  • 批准号:
    10540701
  • 财政年份:
    2021
  • 资助金额:
    $ 50.47万
  • 项目类别:
Metabolic and epigenetic reprogramming of vital organs in SARS-CoV-2 induced systemic toxicity
SARS-CoV-2 引起的全身毒性中重要器官的代谢和表观遗传重编程
  • 批准号:
    10846284
  • 财政年份:
    2021
  • 资助金额:
    $ 50.47万
  • 项目类别:

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  • 批准号:
    81300507
  • 批准年份:
    2013
  • 资助金额:
    22.0 万元
  • 项目类别:
    青年科学基金项目

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  • 批准号:
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