The Role of alternative mRNA polyadenylation in SARS-CoV-2 replication & the host response

替代 mRNA 多聚腺苷酸化在 SARS-CoV-2 复制中的作用

基本信息

  • 批准号:
    10559623
  • 负责人:
  • 金额:
    $ 24.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Determining the role of alternative mRNA polyadenylation in SARS-Cov-2 replication and the host innate immune response SARS-CoV-2 infection has caused the COVID-19 pandemic, and understanding the molecular mechanisms leading to its pathophysiology is a top biomedical priority. In spite of intense research over the last year, we still have much to learn about host factors that promote or restrict SARS-CoV-2 infection and how manipulating them might enable new antiviral treatments. Changes within the infected cell are often mediated by changes in mRNA synthesis that affect not only transcription but also mRNA processing. mRNA precursor is cleaved at its 3’ end and a poly(A) tail added in a process called cleavage and polyadenylation (C/P). If C/P is blocked, mRNA is degraded, poorly exported from the nucleus, and poorly translated. Changing the poly(A) site position, or alternative polyadenylation (APA), affects the type and amount of protein produced from an mRNA. Many viruses have found ways to manipulate C/P and APA to promote viral replication, to interfere with the host antiviral response, or to hijack C/P proteins to augment viral activities. Several screens have demonstrated interaction of C/P proteins with SARS-Cov2 proteins and RNA and identified some C/P proteins as antiviral factors. However, it remains unknown whether SARS-CoV-2 causes changes in poly(A) site usage that support its replication and/or lead to the dysregulation of innate immunity that might contribute to the pathogenic inflammatory response seen in severe COVID-19 cases. By analyzing global pA site usage in cells infected with SARS-CoV-2 using published mRNA-seq data, we found that SARS-CoV-2 infection changes APA of genes involved in immunity, apoptosis, vesicle transport, metabolism, and cell cycle. Based on this preliminary observation, we hypothesize that alterations in C/P caused by SARS-CoV-2 infection influence viral replication and the host antiviral response. To investigate how SARS-CoV-2 affects C/P in host cells and whether targeting the C/P proteins might alter the progression of viral infection, we will 1) determine if C/P is inhibited across the genome during SARS- CoV-2 infection, 2) determine the effects of overexpressing or depleting C/P proteins that regulate APA, and 3) determine if specific viral proteins known to interact with C/P proteins affect 3' end processing. Successful completion of this study will determine if manipulation of C/P has potential as a novel therapeutic target for COVID-19.
确定选择性mRNA聚腺苷化在SARS-Cov-2复制和宿主中的作用

项目成果

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CLAIRE L MOORE其他文献

CLAIRE L MOORE的其他文献

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{{ truncateString('CLAIRE L MOORE', 18)}}的其他基金

The Role of alternative mRNA polyadenylation in SARS-CoV-2 replication & the host response
替代 mRNA 多聚腺苷酸化在 SARS-CoV-2 复制中的作用
  • 批准号:
    10450983
  • 财政年份:
    2022
  • 资助金额:
    $ 24.75万
  • 项目类别:
Defining the Role of Alternative Polyadenylation in Macrophage Differentiation and Function
定义替代多腺苷酸化在巨噬细胞分化和功能中的作用
  • 批准号:
    10577898
  • 财政年份:
    2020
  • 资助金额:
    $ 24.75万
  • 项目类别:
Defining the Role of Alternative Polyadenylation in Macrophage Differentiation and Function
定义替代多腺苷酸化在巨噬细胞分化和功能中的作用
  • 批准号:
    10357895
  • 财政年份:
    2020
  • 资助金额:
    $ 24.75万
  • 项目类别:
Tufts IRACDA
塔夫茨大学 IRACDA
  • 批准号:
    10248365
  • 财政年份:
    2019
  • 资助金额:
    $ 24.75万
  • 项目类别:
Tufts IRACDA
塔夫茨大学 IRACDA
  • 批准号:
    10478087
  • 财政年份:
    2019
  • 资助金额:
    $ 24.75万
  • 项目类别:
Regulation of eukaryotic mRNA polyadenylation by sustained stress
持续应激对真核 mRNA 多腺苷酸化的调节
  • 批准号:
    9055727
  • 财政年份:
    2015
  • 资助金额:
    $ 24.75万
  • 项目类别:
Molecular mechanism of mRNA 3'-end formation in yeast
酵母中mRNA 3端形成的分子机制
  • 批准号:
    7988814
  • 财政年份:
    2009
  • 资助金额:
    $ 24.75万
  • 项目类别:
Training in Education and Critical Research Skills
教育和批判性研究技能培训
  • 批准号:
    7871572
  • 财政年份:
    2009
  • 资助金额:
    $ 24.75万
  • 项目类别:
High throughput screening for anti-fungal drugs that inhibit mRNA polyadenylation
高通量筛选抑制 mRNA 多腺苷酸化的抗真菌药物
  • 批准号:
    7685457
  • 财政年份:
    2008
  • 资助金额:
    $ 24.75万
  • 项目类别:
High throughput screening for anti-fungal drugs that inhibit mRNA polyadenylation
高通量筛选抑制 mRNA 多腺苷酸化的抗真菌药物
  • 批准号:
    7359292
  • 财政年份:
    2008
  • 资助金额:
    $ 24.75万
  • 项目类别:

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