Molecular mechanisms linking viral replication and neuropathogenesis
Molecular mechanisms linking viral replication and neuropathogenesis
批准号:
10660340
负责人:
Priya Shirish Shah
金额:
$39.1万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-02-08 至 2028-01-31
关键词:
AllelesAmino AcidsBiochemicalBiological AssayBrainCell divisionChemicalsCollaborationsCongenital AbnormalityCytomegalovirusDevelopmentDiseaseDrosophila genusEtiologyFetal TissuesFutureGenesGenetic DeterminismGenetic Predisposition to DiseaseGoalsHeadHereditary DiseaseHumanIn VitroIndividualInfectionInheritedIntegration Host FactorsIntellectual functioning disabilityLinkMediatingMethodsMicrocephalyMitosisModelingMolecularMusMutagenesisMutationNeuropathogenesisNonstructural ProteinPathogenesisPathogenicityPathway interactionsPhenotypePhosphorylationPhysiologicalProcessProteinsProteomicsPublishingReplication-Associated ProcessReporterResolutionRoleRubella virusScaffolding ProteinSiteSystemTestingTransgenic OrganismsVariantViralViral PathogenesisVirusVirus ReplicationWorkZIKV infectionZika Virusbrain sizedevelopmental diseasedrug developmentexperimental studyhuman pathogenin vivoinsightknock-downmouse modelmutantmutation screeningnerve stem cellnervous system disorderrecruittherapeutic targetvirus host interaction
中文摘要
项目摘要/摘要
感染发育中的大脑的病毒,包括寨卡病毒、巨细胞病毒和风疹病毒会引起
严重的出生缺陷。小头畸形就是这样一种出生缺陷,它的头部和大脑尺寸严重缩小,
而且常常伴随着智力残疾。这种由病毒引起的神经系统疾病,或称病毒
神经发病机制,可由多种机制引起。最近发现的一种ZIKV非结构方式
蛋白4A(NS4A)通过破坏人类ANKLE2蛋白而导致小头畸形。有趣的是,个人
由于编码ANKLE2的基因发生突变,导致小头畸形。ANKLE2是从蠕虫到
在大脑发育过程中,对协调细胞分裂是必不可少的。ANKLE2派生出此函数
在细胞分裂和发育中通过调节蛋白质的相互作用。NS4A与ANKLE2在物理上相互作用
在果蝇大脑发育模型中以依赖ANKLE2的方式干扰大脑发育。确认2
还会促进ZIKV复制。综上所述,这些研究表明,在寻找宿主蛋白质的过程中
对于复制,ZIKV失调了一条重要的发育途径。因此,NS4A-ANKLE2蛋白
相互作用是研究病毒神经致病机制及其如何与病毒联系的重要模型
分子水平上的复制和遗传性疾病。
这项工作的长期目标是破译病毒-宿主蛋白相互作用如何影响病毒复制和
发病机制,因为这些发现将推动治疗靶点的确定和药物开发。这个
本研究的目的是分析ZIKV NS4A蛋白相互作用的机制。
人类ANKLE2促进ZIKV复制,抑制大脑发育。为了实现这一目标,我们
将检验核心假设,即ANKLE2通过与NS4A和NS4A的相互作用促进病毒复制
通过招募参与ZIKV复制的其他宿主因素到复制站点,这扰乱了生理
ANKLE2蛋白相互作用是大脑发育所必需的。以下具体目标将检验这一假设:
目的1:分析NS4A-ANKLE2蛋白相互作用在ZIKV复制和致病中的作用。
目的2:揭示ANKLE2在ZIKV复制和致病中的分子功能。
当这项工作完成后,这项工作将描绘出单个病毒-宿主蛋白相互作用如何改变发育
促进病毒复制并在分子水平上造成神经疾病的途径。这将揭示
详细的生化洞察病毒与宿主蛋白的相互作用与氨基酸水平的解析,新的宿主因子
在ZIKV复制中发挥作用的蛋白质,以及以前未知的大脑发育关键蛋白
其他遗传性发育障碍。从长远来看,这里建立的方法可以用来
揭示其他具有病毒和遗传病因的疾病背后的分子机制。
英文摘要
PROJECT SUMMARY/ABSTRACT
Viruses that infect the developing brain, including Zika virus (ZIKV), cytomegalovirus, and rubella virus cause
major birth defects. Microcephaly is one such birth defect, in which head and brain size are severely reduced,
and is often accompanied by intellectual disability. This virally-inflicted neurological disease, or viral
neuropathogenesis, can be caused by multiple mechanisms. One recently identified way ZIKV non-structural
protein 4A (NS4A) causes microcephaly is by disrupting the human ANKLE2 protein. Interestingly, individuals
with mutations in the gene encoding ANKLE2 suffer from microcephaly. ANKLE2 is conserved from worms to
humans, and is essential for coordinating cell division during brain development. ANKLE2 derives this function
in cell division and development by mediating protein interactions. NS4A physically interacts with ANKLE2 and
disrupts brain development in an ANKLE2-dependent manner in a fruit fly model of brain development. ANKLE2
also promotes ZIKV replication. Taken together, these studies show that in the process of coopting a host protein
for replication, ZIKV dysregulates an important developmental pathway. Thus, the NS4A-ANKLE2 protein
interaction represents an important model to study viral neuropathogenesis and how it is connected to viral
replication and hereditary disorders at the molecular level.
The long-term goal of this work is to decipher how virus-host protein interactions impact virus replication and
pathogenesis, as these discoveries will fuel therapeutic target identification and drug development. The
objective of this proposal is to dissect the mechanisms by which the protein interaction between ZIKV NS4A
and human ANKLE2 promote ZIKV replication and inhibit brain development. To accomplish this objective, we
will test the central hypothesis that ANKLE2 promotes viral replication through its interaction with NS4A and
by recruiting other host factors involved in ZIKV replication to sites of replication, and this disrupts physiological
ANKLE2 protein interactions required for brain development. The following specific aims will test this hypothesis:
Aim 1: Dissect the impact of the NS4A-ANKLE2 protein interaction in ZIKV replication and pathogenesis.
Aim 2: Unravel the molecular function of ANKLE2 in ZIKV replication and pathogenesis.
When completed, this work will delineate how a single virus-host protein interaction rewires a developmental
pathway to facilitate virus replication and inflict neurological disease at the molecular level. This will reveal
detailed biochemical insight into a virus-host protein interaction with amino acid-level resolution, new host factors
that play a role in ZIKV replication, and previously unknown proteins key to brain development and disrupted in
other hereditary developmental disorders. In the long term, the methods established here could be employed to
uncover the molecular mechanisms behind other diseases with viral and hereditary etiologies.
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会议论文
Molecular mechanisms linking viral replication and neuropathogenesis
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批准号:10673233
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项目类别:
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资助金额:$52.82万
-
财政年份:2022
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负责人:Priya Shirish Shah
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依托单位:
Conserved molecular mechanisms of replication for mosquito-borne flaviviruses
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批准号:10431689
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项目类别:
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资助金额:$19.94万
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财政年份:2022
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负责人:Priya Shirish Shah
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依托单位:
Conserved molecular mechanisms of replication for mosquito-borne flaviviruses
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批准号:10577854
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项目类别:
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资助金额:$24.03万
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财政年份:2022
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依托单位:
A vertebrate model of viral and hereditary microcephaly
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批准号:10576107
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项目类别:
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资助金额:$15.99万
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财政年份:2022
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负责人:Priya Shirish Shah
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Quantitative mapping of interactions between dengue virus and its hosts
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批准号:8918261
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项目类别:
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资助金额:$5.8万
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财政年份:2015
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负责人:Priya Shirish Shah
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依托单位:
Quantitative mapping of interactions between dengue virus and its hosts
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批准号:8783961
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项目类别:
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资助金额:$5.51万
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财政年份:2015
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负责人:Priya Shirish Shah
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依托单位:
海外基金