Structural characterization of native HBV capsids and virions from human cells

人类细胞天然 HBV 衣壳和病毒颗粒的结构表征

基本信息

  • 批准号:
    10736669
  • 负责人:
  • 金额:
    $ 72.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-14 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Hepatitis B virus (HBV) infection is a global public health concern. Despite effective vaccines to prevent this disease, current approved treatment rarely leads to a complete cure. There is an unmet medical need for developing new therapeutics for HBV infection that can lead to a sustained response. Targeting HBV capsid assembly process has become an emerging strategy for developing new antiviral treatment for HBV. However, many efforts have been made by using different capsid protein (Cp) constructs expressed in Escherichia coli to mimic or reconstitute native-like viral particles. Yet, these structures cannot correctly represent the native HBV conformations due to the lacks of nucleic acid binding domain of the Cp, viral genome, and viral enzymes, all of which are required for viral replication. Furthermore, the lack of post translational modifications of the Cp also hampers the interpretation between observed Cp structures to the biomedical data obtained from the mammalian cell culture system or experimental animals. To date there is no available high-resolution native HBV structures, which is a major gap in knowledge of the HBV field. In this proposal, we aim to use cryo-electron microscope (cryo-EM) to directly characterize the structures of native HBV capsids and virions from human cells. In Aim 1, we will determine the high-resolution structures of purified intracellular HBV capsids with different types of viral genome. We will address the key questions concerning the structural dynamics of HBV capsids during genome maturation. We will also determine the structure of the HBV reverse transcriptase (RT) and its location during reverse transcription to help understand its mode of action (whether the RT is static or moves). In Aim 2, we will investigate the high-resolution structures of secreted HBV virions. This aim will address the questions concerning how HBV capsids interact with the viral envelop proteins. Finally, experimental findings from these two Aims will be integrated to elucidate capsid dynamics during HBV replication and illuminate the molecular determinant(s) of HBV envelopment. This proposal is expected to solve 4 types of intracellular HBV capsid structures (empty, RNA-filled, single- stranded DNA-filled, and mature partially double-stranded DNA-filled capsids) and 3 secreted enveloped HBV virion structures (empty, mature, and prematurely secreted virions) using cryo-EM to define the conformational changes of the capsid during viral replication, particularly in the context of different viral genome forms and interactions between the capsid and surface proteins. The methodology exploits appropriate mutations of Cp and RT to ensure obtaining homogenous particles of the various types as described above, which can be further computationally classified to minimize cross-contamination. Understanding the native HBV structures will provide valuable new information for HBV biology and guide the design of novel antiviral drugs in the future. The project is anticipated to impact fields ranging from HBV, molecular virology, antiviral drug development, and macromolecular structure and function.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Che-Yen Wang其他文献

Che-Yen Wang的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Che-Yen Wang', 18)}}的其他基金

Dissecting Structural Details of Hepadnavirus Subviral Particles
剖析嗜肝DNA病毒亚病毒颗粒的结构细节
  • 批准号:
    10287141
  • 财政年份:
    2021
  • 资助金额:
    $ 72.8万
  • 项目类别:
Dissecting Structural Details of Hepadnavirus Subviral Particles
剖析嗜肝DNA病毒亚病毒颗粒的结构细节
  • 批准号:
    10407642
  • 财政年份:
    2021
  • 资助金额:
    $ 72.8万
  • 项目类别:

相似海外基金

Development of decellularized small-diameter arterial grafts and evaluation in large animal experiments
脱细胞小直径动脉移植物的研制及大动物实验评价
  • 批准号:
    21H03016
  • 财政年份:
    2021
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Developing and validating a computational model of the gut microbiota-mucosa interactions to replace and reduce animal experiments
开发和验证肠道微生物群-粘膜相互作用的计算模型,以取代和减少动物实验
  • 批准号:
    NC/R001707/1
  • 财政年份:
    2018
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Training Grant
Developing and validating a computational model of the gut microbiota-mucosa interactions to replace and reduce animal experiments
开发和验证肠道微生物群-粘膜相互作用的计算模型,以取代和减少动物实验
  • 批准号:
    2103295
  • 财政年份:
    2018
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Studentship
Research on the way of information transmission to gain social understanding of animal experiments
动物实验获得社会理解的信息传递方式研究
  • 批准号:
    16K07080
  • 财政年份:
    2016
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
CDS&E: Modeling the Zebrafish Model Organism Toward Reducing, Refining, and Replacing Animal Experiments
CDS
  • 批准号:
    1505832
  • 财政年份:
    2015
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Standard Grant
Never replicate a successful experiment? Standardization, heterogenization and reproducibility in animal experiments
从未复制过成功的实验?
  • 批准号:
    283089959
  • 财政年份:
    2015
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Research Grants
Arrhythmogenic Drug Evaluation System by Simplified Animal Experiments
简化动物实验的致心律失常药物评价系统
  • 批准号:
    26350520
  • 财政年份:
    2014
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Promotion of the 4Rs in animal experiments by the development of a production process for polyclonal antibodies using a goldfish
开发金鱼多克隆抗体生产工艺,促进动物实验中的4R
  • 批准号:
    23650227
  • 财政年份:
    2011
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Development of microangiographic systems to visualize cerebular perforating artery in clinical settings and retrobulbar ophthalmic artery arteries in animal experiments.
开发显微血管造影系统,以在临床环境中可视化小脑穿支动脉,并在动物实验中可视化球后眼动脉。
  • 批准号:
    23390305
  • 财政年份:
    2011
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
The study for the modification of cerebral synapses by balance exercises in the elderly based on animal experiments.
基于动物实验的老年人平衡运动改变大脑突触的研究。
  • 批准号:
    21500471
  • 财政年份:
    2009
  • 资助金额:
    $ 72.8万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了