Determining mechanisms of innate immune modulation by ADP-ribosylation
通过 ADP-核糖基化确定先天免疫调节机制
基本信息
- 批准号:10386112
- 负责人:
- 金额:$ 3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:ADP Ribose TransferasesADP ribosylationAddressAdenosine Diphosphate RiboseAffectAntiviral AgentsAntiviral ResponseAntiviral TherapyAutomobile DrivingBiological ProcessBiologyCell Culture TechniquesCellsChiropteraCommunicable DiseasesCoronavirusFamilyFoundationsGoalsHydrolaseHypersensitivityImmune responseImpairmentInfectionInnate Immune ResponseInterferonsKnock-outKnowledgeLeadMalignant NeoplasmsMediatingMissionModelingMurine hepatitis virusNational Institute of General Medical SciencesPathway interactionsPhenotypePhosphorylationPost-Translational Protein ProcessingProcessProteinsRNA replicationResearchResearch PersonnelRoleSystemTogaviridaeTranslationsViralViral hepatitisVirusVirus DiseasesVirus ReplicationWorkhuman diseaseimmunoregulationinhibitor/antagonistinnate immune mechanismsinnovationmutantnovelpathogenic virusprotein functionresponse
项目摘要
PROJECT SUMMARY
ADP-ribosylation is an important post-translational modification that directly influences several
biological processes including cancer, allergy, and infectious disease. ADP-ribose can be added to proteins as
one or more consecutive units by ADP-ribosyltransferases, also termed PARPs, resulting in mono- or poly-
ADP-ribosylation (mAR or pAR). Most mARylating PARPs are upregulated by interferon (IFN) upon virus
infection and several are predicted to have antiviral functions. In addition, several viral families, including the
Coronaviridae and Togaviridae, encode for macrodomain proteins that have mono-ADP-ribosyl hydrolase
(ARH) activity. This activity allows these viruses the ability to specifically counteract the effects of mAR, further
implicating mAR in the mammalian antiviral response. Despite these findings, there are only a few known
examples where mAR is known to inhibit virus replication. This is largely due to the lack of cell culture models
of virus infections where the mAR status of a cell can be specifically controlled, such as models using mutant
viruses or PARP knockout cells that have significant phenotypes. Importantly, the PI has established a virus
infection system using a model coronavirus, Murine Hepatitis Virus (MHV), where virus lacking ARH activity is
i) significantly impaired in virus replication and ii) independently induces a robust IFN response. These
phenotypes are reversed by PARP inhibitors, establishing mAR as a key factor driving this anti-viral response.
The investigator’s long-term goal is to determine mechanistically how mAR inhibits virus replication and
enhances the innate immune response following virus infection. This gap in knowledge will be resolved by
answering the following questions: 1) How does mAR inhibit MHV infection? Does it inhibit the entry, RNA
replication, protein translation, assembly, or release of MHV? 2) What step(s) of the IFN induction pathway is
enhanced by mAR, and does mAR also affect the IFN response in bats, which are known to harbor many
highly pathogenic viruses? 3) What proteins are modified by PARPs following virus infection and which
substrates are relevant for specific phenotypes? The rationale for this research is that it will enhance our
understanding of mAR, including its ability to modulate protein function and will uncover novel cellular proteins
or processes that mediate virus replication. The work is innovative because: i) it will bridge a significant
knowledge gap between ADP-ribose biology, the innate immune response, and virus replication; ii) it utilizes
unique models of infection utilizing both mutant viruses and PARP knockout cells; and iii) will be the first to
address the role of mAR in bats. Finally, these projects are significant and relevant to the NIGMS mission
because they will provide a thorough understanding of how mAR impacts the anti-viral response that could lay
the foundation for advances in the treatment of virus infections or other human diseases impacted by mAR.
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)
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Anthony R Fehr其他文献
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{{ truncateString('Anthony R Fehr', 18)}}的其他基金
Determining mechanisms of innate immune modulation by ADP-ribosylation
通过 ADP-核糖基化确定先天免疫调节机制
- 批准号:
10027966 - 财政年份:2020
- 资助金额:
$ 3万 - 项目类别:
Determining mechanisms of innate immune modulation by ADP-ribosylation
通过 ADP-核糖基化确定先天免疫调节机制
- 批准号:
10256655 - 财政年份:2020
- 资助金额:
$ 3万 - 项目类别:
Investigating How ADP-ribosylation Impacts Innate Immunity During Coronavirus Infection
研究 ADP-核糖基化如何影响冠状病毒感染期间的先天免疫
- 批准号:
9428897 - 财政年份:2018
- 资助金额:
$ 3万 - 项目类别:
Deciphering the Role of the Coronavirus Macro Domain in SARS-CoV Infection
破译冠状病毒宏结构域在 SARS-CoV 感染中的作用
- 批准号:
8781200 - 财政年份:2014
- 资助金额:
$ 3万 - 项目类别:
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