Biogenesis and operation of the human cytomegalovirus assembly complex

人类巨细胞病毒组装复合物的生物合成和操作

基本信息

  • 批准号:
    8535921
  • 负责人:
  • 金额:
    $ 37.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-17 至 2014-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is the herpesvirus of greatest public health and medical significance in the US. In addition to its societal importance as a human pathogen, the aspects of human biology "learned" by the virus during its co-evolution with humans have enabled development of HCMV into an extraordinarily valuable model microbe that has helped to reveal many aspects of virus-host interactions in the areas of immunology, molecular biology, and cell biology. The HCMV cytoplasmic virion assembly complex (cVAC) is a structure about the size of a nucleus where developing virions acquire most of their tegument, are enveloped, and are then transported to the cell surface for release. cVAC biogenesis involves dramatic cytoplasmic remodeling that takes place during the first 2 to 4 days after infection. We found that the cVAC is arranged as a set of nested cylinders, with the outer cylinder consisting of networks of tubular vesicles derived from the Golgi apparatus and the trans-Golgi network; the inner cylinder consists of vesicles derived from recycling endosomes where virions are enveloped and then transported to the cell surface. From quantitative analyses of the distribution of markers for various components of the secretory and endosomal machinery, we identified striking examples of HCMV-induced shifts in the identities of organelles involved in protein transport, and we have identified three HCMV genes as candidate regulators of cVAC biogenesis. Our central hypothesis is that HCMV proteins orchestrate creation of the cVAC via interactions of viral proteins with cellular proteins and organelles to optimize infectious virion production and egress. To test this hypothesis, in Aim 1, we will define the roles of the virus genes we have identified as candidate regulators of cVAC biogenesis and use them as probes to delineate the molecular pathway that results in assembly of the cVAC. In Aim 2, we will determine how the reorganized secretory organelles and machinery contribute to the process of virion assembly and maturation. We will employ recombinant viruses to express candidate viral and cellular regulatory proteins that have been engineered to contain protein destabilization domains, enabling either destruction or restabilization of the protein of interest at desired times during cVAC biogenesis and virus replication. We will then use a battery of assays to measure the effects on virus replication, and to compare the functions of the affected organelles and machinery with and without inactivation of the regulator of interest. Our studies will result in (i) illumination of the process of virion maturation and how HCMV manages cellular systems for its benefit, (ii) definition of new targets for development of novel antiviral compounds, and (iii) new insights into the mechanisms that regulate the biogenesis of cellular protein transport and processing organelles.
描述(由申请人提供):人类巨细胞病毒(HCMV)是在美国具有最大公共卫生和医学意义的疱疹病毒。除了作为人类病原体的社会重要性外,病毒在与人类共同进化过程中“习得”的人类生物学特性使得 HCMV 能够发展成为一种非常有价值的模型微生物,有助于揭示免疫学、分子生物学和细胞生物学领域中病毒与宿主相互作用的许多方面。 HCMV 细胞质病毒粒子组装复合体 (cVAC) 是一种与细胞核大小相当的结构,发育中的病毒粒子在其中获得大部分外皮,被包膜,然后被转运到细胞表面释放。 cVAC 生物发生涉及感染后 2 至 4 天内发生的剧烈细胞质重塑。我们发现cVAC排列成一组嵌套的圆柱体,外圆柱体由源自高尔基体和跨高尔基体网络的管状囊泡网络组成;内圆柱体由回收内体衍生的囊泡组成,病毒颗粒被包裹在囊泡中,然后被运输到细胞表面。通过对分泌和内体机制各个组成部分的标记分布的定量分析,我们发现了 HCMV 诱导的参与蛋白质转运的细胞器身份转变的惊人例子,并且我们已经确定了三个 HCMV 基因作为 cVAC 生物发生的候选调节因子。我们的中心假设是,HCMV 蛋白通过病毒蛋白与细胞蛋白和细胞器的相互作用来协调 cVAC 的产生,以优化感染性病毒颗粒的产生和排出。为了检验这一假设,在目标 1 中,我们将定义我们已确定为 cVAC 生物合成候选调节因子的病毒基因的作用,并使用它们作为探针来描绘导致 cVAC 组装的分子途径。在目标 2 中,我们将确定重组的分泌细胞器和机器如何促进病毒粒子组装和成熟的过程。我们将采用重组病毒来表达候选病毒和细胞调节蛋白,这些蛋白经过工程改造,含有蛋白不稳定结构域,从而能够在 cVAC 生物发生和病毒复制过程中的所需时间破坏或重新稳定目标蛋白。然后,我们将使用一系列测定来测量对病毒复制的影响,并比较受影响的细胞器和机器在感兴趣的调节器失活和不失活的情况下的功能。我们的研究将导致(i)阐明病毒粒子成熟的过程以及HCMV如何管理细胞系统以使其受益,(ii)定义开发新型抗病毒化合物的新靶标,以及(iii)对调节细胞蛋白质运输和加工细胞器的生物发生机制的新见解。

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 }}

PHILIP E PELLETT其他文献

PHILIP E PELLETT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('PHILIP E PELLETT', 18)}}的其他基金

Segmented expression of a human cytomegalovirus-encoded heptaspanning protein
人巨细胞病毒编码的七跨蛋白的分段表达
  • 批准号:
    7354499
  • 财政年份:
    2008
  • 资助金额:
    $ 37.48万
  • 项目类别:
Development of the human cytomegalovirus assembly complex
人类巨细胞病毒组装复合物的开发
  • 批准号:
    7686750
  • 财政年份:
    2008
  • 资助金额:
    $ 37.48万
  • 项目类别:
Segmented expression of a human cytomegalovirus-encoded heptaspanning protein
人巨细胞病毒编码的七跨蛋白的分段表达
  • 批准号:
    7612123
  • 财政年份:
    2008
  • 资助金额:
    $ 37.48万
  • 项目类别:
Development of the human cytomegalovirus assembly complex
人类巨细胞病毒组装复合物的开发
  • 批准号:
    7354642
  • 财政年份:
    2008
  • 资助金额:
    $ 37.48万
  • 项目类别:
Regulation of MicroRNA by Human Cytomegalovirus
人类巨细胞病毒对 MicroRNA 的调控
  • 批准号:
    7619104
  • 财政年份:
    2007
  • 资助金额:
    $ 37.48万
  • 项目类别:
Regulation of MicroRNA by Human Cytomegalovirus
人类巨细胞病毒对 MicroRNA 的调控
  • 批准号:
    7499628
  • 财政年份:
    2007
  • 资助金额:
    $ 37.48万
  • 项目类别:

相似海外基金

Development of a new generation of antiviral agents that are effective against drug-resistant viruses and prevent serious illness and sequelae.
开发新一代抗病毒药物,可有效对抗耐药病毒并预防严重疾病和后遗症。
  • 批准号:
    23K18186
  • 财政年份:
    2023
  • 资助金额:
    $ 37.48万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents
一个多功能的基于结构的治疗平台,用于开发基于 VHH 的抗毒素和抗病毒药物
  • 批准号:
    10560883
  • 财政年份:
    2023
  • 资助金额:
    $ 37.48万
  • 项目类别:
Genetically encoded bicyclic peptide libraries for the discoveryof novel antiviral agents
用于发现新型抗病毒药物的基因编码双环肽库
  • 批准号:
    10730692
  • 财政年份:
    2021
  • 资助金额:
    $ 37.48万
  • 项目类别:
Design and synthesis of nucleosides to develop antiviral agents and oligonucleotide therapeutics
设计和合成核苷以开发抗病毒药物和寡核苷酸疗法
  • 批准号:
    21K06459
  • 财政年份:
    2021
  • 资助金额:
    $ 37.48万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Genetically encoded bicyclic peptide libraries for the discoveryof novel antiviral agents
用于发现新型抗病毒药物的基因编码双环肽库
  • 批准号:
    10189880
  • 财政年份:
    2021
  • 资助金额:
    $ 37.48万
  • 项目类别:
Computer-aided identification and synthesis of novel broad-spectrum antiviral agents
新型广谱抗病毒药物的计算机辅助鉴定和合成
  • 批准号:
    2404261
  • 财政年份:
    2020
  • 资助金额:
    $ 37.48万
  • 项目类别:
    Studentship
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10222540
  • 财政年份:
    2020
  • 资助金额:
    $ 37.48万
  • 项目类别:
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10669717
  • 财政年份:
    2020
  • 资助金额:
    $ 37.48万
  • 项目类别:
Association between sedentary lifestyle and liver cancer development in hepatitis C patients treated with direct-acting antiviral agents
接受直接抗病毒药物治疗的丙型肝炎患者久坐的生活方式与肝癌发展之间的关系
  • 批准号:
    20K10713
  • 财政年份:
    2020
  • 资助金额:
    $ 37.48万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection
基于对 SARS-CoV-2 感染的先天免疫反应,开发针对 COVID-19 的广谱抗病毒药物
  • 批准号:
    10174522
  • 财政年份:
    2020
  • 资助金额:
    $ 37.48万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了