Reverse transcriptase-mediated expansion of the host innate immune system
逆转录酶介导的宿主先天免疫系统扩张
基本信息
- 批准号:10574416
- 负责人:
- 金额:$ 23万
- 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:2022-12-12 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:APOCEC3G geneAllelesAnimalsAntiviral ResponseBackBindingBiochemistryBiological AssayBirthCebidaeCellsCommunicable DiseasesComputational BiologyDataDependenceDimerizationDisease OutcomeDisease susceptibilityDisparateDominant-Negative MutationEEF1A1 geneElongation FactorExonsExpression ProfilingFamilyFrequenciesGene DuplicationGene FamilyGenesGenetic DeterminismGenetic PolymorphismGenetic TranscriptionGenomeHaploidyHaplotypesHeritabilityHumanHuman GenomeImmuneImmune responseImmunityIn VitroIndividualInnate Immune SystemInterferonsInvadedKnock-outLinkLocationMapsMeasuresMediatingMessenger RNAMutationNatural ImmunityOutcomePeptide FragmentsPeptidesPhasePongidaePopulationPredispositionPrimatesProcessProteinsPseudogenesPublishingRNA VirusesRNA-Directed DNA PolymeraseRecording of previous eventsResearchResistanceRetroviridaeRetroviridae InfectionsReverse TranscriptionRoleShapesSignal TransductionSourceTechnologyTestingTissuesTranslatingTranslationsVariantViralViral GenesViral PhysiologyVirusVirus DiseasesVirus Replicationcell typecofactordimergene interactiongenome analysishigh throughput screeninghuman reference genomeimmune system functionindividual variationinhibitorinnate immune functioninsertion/deletion mutationpathogenpromoterprospectivetranscription factorvirology
项目摘要
PROJECT SUMMARY
Large effect mutations in innate immunity genes can have dramatic effects on infectious disease susceptibility
and outcome. In addition, the genetic determinants of more subtle and widespread variation in an individual’s
susceptibility and immune response to viral infections has been studied in the context of mutations in the many
known innate immunity genes. We propose that there are new polymorphic innate immune genes created by
retroviruses (so called ‘retrocopies’) in the genome of many individuals which are typically overlooked, and which
have the capacity to modulate an individual’s immune response. Thousands of young and old retrocopies are
present in each human genome and their number and sequences differ among individuals in a population. Until
now, old retrocopies have largely been ignored as pseudogenes, while young retrocopies have been
understudied due to technical challenges of accurate identification inherent in the most common sequencing
technologies. A pioneering study in our lab showed that human and other primate genomes contain retrocopies
of the APOBEC3 family of viral restriction factors that are transcribed and capable of restricting virus replication
in vitro. Our more recent preliminary data revealed extensive retrocopying of additional antiviral gene families
within humans and other primate species, suggesting the recent retrocopying of viral restriction and host
dependency factors may be widespread. Further, some of these retrocopies are very young – present in only
some humans – and could represent an unappreciated source of individual variation in susceptibility or
resistance to viral infection. With a combination of computational biology, in vitro virology and biochemistry, and
high throughput functional assays, we will identify young retrocopies of virus-interacting genes that are present
in only some humans and test these new genes’ ability to enhance or impede the innate immune system’s
antiviral response. To test our hypothesis that retrocopy expansions modify immune system function, we will: (1)
Identify young, polymorphic retrocopies of host dependency and restriction factor genes in humans. (2)
Characterize transcription and antiviral functions of polymorphic host dependency and restriction factor
retrocopies, either as restriction factors or dependency factors that evade viral co-option. (3) Identify retrocopies
that act as dominant negative inhibitors of their parental antiviral genes thereby inhibiting the innate immune
system and promoting viral replication. This research will discover new innate immune genes and found a new
direction in understanding the genetic determinants of an individual's susceptibility and immune response to
virus infection.
项目摘要
先天免疫基因的大效应突变对感染性疾病的易感性有显著影响
和结果。此外,在一个人的基因中,
对病毒感染的易感性和免疫反应已经在许多基因突变的背景下进行了研究。
已知的先天免疫基因我们提出,有新的多态性先天免疫基因的创造,
逆转录病毒(所谓的“逆转录病毒”)在许多人的基因组中通常被忽视,
有能力调节个体的免疫反应。数以千计的年轻人和老年人
存在于每个人类基因组中,并且它们的数量和序列在群体中的个体之间不同。直到
现在,旧的逆转录复制物在很大程度上被当作假基因而被忽视,而年轻的逆转录复制物则被认为是假基因。
由于在最常见的测序中固有的准确鉴定的技术挑战,
技术.我们实验室的一项开创性研究表明,人类和其他灵长类动物基因组包含逆转录复制
转录并能够限制病毒复制的病毒限制因子的APOBEC 3家族
体外我们最近的初步数据揭示了额外的抗病毒基因家族的广泛的逆转录
在人类和其他灵长类动物物种中,这表明最近病毒限制和宿主
依赖性因素可能很普遍。此外,其中一些复刻是非常年轻的-目前只有在
一些人-并且可能代表易感性个体差异的未被认识的来源,
抵抗病毒感染。结合计算生物学、体外病毒学和生物化学,
高通量功能测定,我们将确定年轻的逆转录病毒相互作用基因,
并测试这些新基因增强或阻碍先天免疫系统的能力。
抗病毒反应为了验证我们的假设,即逆转录扩增改变免疫系统功能,我们将:(1)
识别人类宿主依赖性和限制因子基因的年轻多态性逆转录。(二更)
多态性宿主依赖性和限制性因子的转录和抗病毒功能
逆转录,无论是作为限制因素或依赖性因素,逃避病毒的共同选择。(3)识别追溯副本
其作为其亲本抗病毒基因的显性负抑制剂,从而抑制先天免疫,
系统和促进病毒复制。这项研究将发现新的先天免疫基因,
在理解一个人的易感性和免疫反应的遗传决定因素的方向,
病毒感染。
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)
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Richard Noel McLaughlin其他文献
Richard Noel McLaughlin的其他文献
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{{ truncateString('Richard Noel McLaughlin', 18)}}的其他基金
Leveraging natural and directed evolution to dissect the functional consequences of sequence variation in human L1 retrotransposons
利用自然和定向进化来剖析人类 L1 逆转录转座子序列变异的功能后果
- 批准号:
10817319 - 财政年份:2021
- 资助金额:
$ 23万 - 项目类别:
Leveraging natural and directed evolution to dissect the functional consequences of sequence variation in human L1 retrotransposons
利用自然和定向进化来剖析人类 L1 逆转录转座子序列变异的功能后果
- 批准号:
10275297 - 财政年份:2021
- 资助金额:
$ 23万 - 项目类别:
Leveraging natural and directed evolution to dissect the functional consequences of sequence variation in human L1 retrotransposons
利用自然和定向进化来剖析人类 L1 逆转录转座子序列变异的功能后果
- 批准号:
10634618 - 财政年份:2021
- 资助金额:
$ 23万 - 项目类别:
Leveraging natural and directed evolution to dissect the functional consequences of sequence variation in human L1 retrotransposons
利用自然和定向进化来剖析人类 L1 逆转录转座子序列变异的功能后果
- 批准号:
10470839 - 财政年份:2021
- 资助金额:
$ 23万 - 项目类别:
Causes and human health consequences of the evolution of retroelements and host restriction factors
逆转录因子和宿主限制因子进化的原因和人类健康后果
- 批准号:
8968153 - 财政年份:2015
- 资助金额:
$ 23万 - 项目类别:
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