Targeting the host NDP kinase to abrogate viral dissemination
靶向宿主 NDP 激酶以消除病毒传播
基本信息
- 批准号:10223818
- 负责人:
- 金额:$ 13.63万
- 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:2020-07-27 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAntiviral AgentsBCL2 geneBiochemistryBiological AssayBiologyCell Culture TechniquesCellsClinicalCollaborationsComplexDevelopmentDiseaseDrug resistanceEstrogen receptor positiveFDA approvedGene ActivationGenesGeneticGenotypeGlycoproteinsGoalsGolgi ApparatusGuanosine TriphosphateGuanosine Triphosphate PhosphohydrolasesHerpesviridaeHerpesviridae InfectionsHomologous GeneHousekeeping GeneHumanHuman Herpesvirus 8ImmuneImpairmentIndividualIntegration Host FactorsIntracellular TransportKaposi SarcomaLife Cycle StagesLytic PhaseMediatingMembraneModelingMolecularMorbidity - disease rateMorphogenesisMutationNME1 geneNucleoside Diphosphate Kinase ANucleoside-Diphosphate KinasePathogenesisPathway interactionsPenetrancePhosphotransferasesPhysiologicalProcessProductionProtein IsoformsProteinsRegulationResearchRoleSiteSystemTestingTherapeuticTherapeutic IndexTreatment EfficacyVaccinesValidationVesicleViralViral GenesViral ProteinsVirionVirulentVirusVirus AssemblyWorkcombatdesigngammaherpesvirushigh resolution imaginghuman pathogenin vivoinhibitor/antagonistinsightinterdisciplinary approachlive cell imaginglytic replicationmortalitynucleoside triphosphateparticleprotein transportreverse geneticssmall moleculesmall molecule inhibitorsmall molecule librariestraffickingvesicle transportviral transmissionvirus envelope
项目摘要
Project Summary
There is an urgent and unmet need for the development of safe and effective therapeutics against serious
human pathogens such as Kaposi's sarcoma herpesvirus (KSHV), which causes significant morbidity and
mortality in immune-compromised individuals and remains a clinical challenge. Currently, no FDA approved
therapeutics or vaccines are available for KSHV infection. Given that KSHV and other human herpesviruses
hijack host proteins and pathways to complete their replication cycles and spread from cell to cell, strategies
targeting these pathways and mechanisms will provide broad-spectrum genotype coverage and a high barrier
to drug resistance. Herpesviruses including KSHV have long been known to exploit the COPII-mediated
secretory pathway for their maturation. However, the mechanisms governing this process remain less
understood. This project will fill this gap, capitalizing on our recent discovery that the host nucleoside
diphosphates kinase NM23-H2, an important regulator of COPII vesicle transport, is exploited by KSHV for
their virion morphogenesis and egress. We found that viral Bcl-2 of KSHV (ks-Bcl-2) directly interacted with,
stabilized, and activated NM23-H2 during lytic phase of KSHV. Loss of NM23-H2 or mutations in ks-Bcl-2 that
abolished NM23-H2 interaction severely impaired virion production. We thus hypothesize that KSHV activates
host protein NM23-H2 to exploit the COPII pathway for efficient virion assembly and release, unraveling
a key checkpoint in virus lifecycle that can be targeted for new antiviral therapeutics. We now bring
within this proposal a collaboration of experts in KSHV biology and in design of small-molecule inhibitors to
identify cellular pathway responsible for virion production of KSHV and develop a new strategy to dampen virus
transmission. To achieve this goal, we propose two specific aims, including (1) defining the molecular
mechanism by which KSHV ks-Bcl-2 targets NM23-H2 to activate Sar1-mediated COPII transport for efficient
virion assembly; and (2) targeting ks-Bcl-2-NM23-H2-mediated COPII mechanism to block KSHV propagation.
These aims will be addressed using multidisciplinary approaches that integrate state-of-the-art genetic,
biochemistry, live-cell imaging, and physiological assays. Together, we anticipate that our studies will identify
host genes/pathways that function in virus assembly and egress, and provide compelling in vivo validation that
targeting NM23-H2-dependent host mechanism can abrogate virus transmission within and between
individuals.
项目摘要
迫切需要开发针对严重肿瘤的安全有效的治疗方法,
人类病原体,如卡波西肉瘤疱疹病毒(KSHV),其导致显著的发病率,
免疫受损个体的死亡率,并且仍然是临床挑战。目前,没有FDA批准
治疗剂或疫苗可用于KSHV感染。鉴于KSHV和其他人类疱疹病毒
劫持宿主蛋白质和途径以完成其复制周期并在细胞间传播,
针对这些途径和机制将提供广谱基因型覆盖和高屏障,
to drug药物resistance抗性.长期以来,已知包括KSHV在内的疱疹病毒利用COPII介导的免疫抑制作用。
成熟的分泌途径。然而,管理这一过程的机制仍然较少,
明白这个项目将填补这一空白,利用我们最近的发现,
二磷酸激酶NM 23-H2是COPII囊泡转运的重要调节剂,被KSHV利用,
它们的病毒体形态发生和扩散我们发现KSHV的病毒Bcl-2(ks-Bcl-2)直接与,
在KSHV的裂解期稳定并活化NM 23-H2。NM 23-H2缺失或ks-Bcl-2突变,
NM 23-H2相互作用的消失严重损害了病毒体的产生。因此,我们假设KSHV激活
宿主蛋白NM 23-H2利用COPII途径进行有效的病毒体组装和释放,解开
病毒生命周期中的一个关键检查点,可用于新的抗病毒治疗。我们现在带来
在该提案中,KSHV生物学和小分子抑制剂设计方面的专家合作,
确定负责KSHV病毒体产生细胞途径并开发抑制病毒的新策略
传输为了实现这一目标,我们提出了两个具体目标,包括(1)定义分子
KSHV ks-Bcl-2靶向NM 23-H2激活Sar 1介导的COPII转运的机制,
(2)靶向ks-Bcl-2-NM 23-H2介导的COPII机制以阻断KSHV增殖。
这些目标将使用多学科方法来实现,这些方法整合了最先进的遗传学、
生物化学、活细胞成像和生理学测定。总之,我们预计我们的研究将确定
宿主基因/途径在病毒装配和外出中发挥作用,并提供令人信服的体内验证,
靶向NM 23-H2依赖性宿主机制可以消除病毒在宿主内和宿主间的传播
个体
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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Chengyu Liang其他文献
Chengyu Liang的其他文献
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{{ truncateString('Chengyu Liang', 18)}}的其他基金
New control of oncogene activation in T-cell leukemia
T细胞白血病癌基因激活的新控制
- 批准号:
10609073 - 财政年份:2022
- 资助金额:
$ 13.63万 - 项目类别:
New control of oncogene activation in T-cell leukemia
T细胞白血病癌基因激活的新控制
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10443113 - 财政年份:2022
- 资助金额:
$ 13.63万 - 项目类别:
Molecular Mechanism of UV Protection in Cutaneous Melanoma
皮肤黑色素瘤紫外线防护的分子机制
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10294255 - 财政年份:2020
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$ 13.63万 - 项目类别:
A cancer-derived truncating mutation in disease penetrance and progression of MSI CRC
MSI CRC 疾病外显率和进展中癌症衍生的截短突变
- 批准号:
10264124 - 财政年份:2020
- 资助金额:
$ 13.63万 - 项目类别:
Molecular Mechanism of UV Protection in Cutaneous Melanoma
皮肤黑色素瘤紫外线防护的分子机制
- 批准号:
10542439 - 财政年份:2020
- 资助金额:
$ 13.63万 - 项目类别:
A cancer-derived truncating mutation in disease penetrance and progression of MSI CRC
MSI CRC 疾病外显率和进展中癌症衍生的截短突变
- 批准号:
10320079 - 财政年份:2020
- 资助金额:
$ 13.63万 - 项目类别:
A cancer-derived truncating mutation in disease penetrance and progression of MSI CRC
MSI CRC 疾病外显率和进展中癌症衍生的截短突变
- 批准号:
10517499 - 财政年份:2020
- 资助金额:
$ 13.63万 - 项目类别:
Molecular Mechanism of UV Protection in Cutaneous Melanoma
皮肤黑色素瘤紫外线防护的分子机制
- 批准号:
10318542 - 财政年份:2020
- 资助金额:
$ 13.63万 - 项目类别:
A cancer-derived truncating mutation in disease penetrance and progression of MSI CRC
MSI CRC 疾病外显率和进展中癌症衍生的截短突变
- 批准号:
10230378 - 财政年份:2020
- 资助金额:
$ 13.63万 - 项目类别:
Molecular Mechanism of UV Protection in Cutaneous Melanoma
皮肤黑色素瘤紫外线防护的分子机制
- 批准号:
10225017 - 财政年份:2020
- 资助金额:
$ 13.63万 - 项目类别:
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