Investigation of Synthetic DNA-based Viral Particles for Spatially Controlled Antigen Presentation
基于 DNA 的合成病毒颗粒空间控制抗原呈递的研究
基本信息
- 批准号:10662377
- 负责人:
- 金额:$ 38.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-02 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcquired Immunodeficiency SyndromeAdjuvantAffinityAgonistAnimal ModelAntibody AffinityAntibody FormationAntigen PresentationAntigen-Presenting CellsAntigensArtificial nanoparticlesB-Cell ActivationB-Cell Antigen ReceptorB-Cell Receptor BindingB-LymphocytesBathingBenchmarkingBiodistributionBiological AssayBiomedical EngineeringCalcium SignalingCell modelCellsCellular ImmunityCharacteristicsCommunicable DiseasesConfocal MicroscopyCuesDNADevelopmentDimensionsEngineeringEnsureEvaluationEventHIVHIV Envelope Protein gp120HIV InfectionsHIV envelope proteinHIV vaccineHIV-1HealthHepatitis B VaccinesHeterogeneityHumanHuman Papilloma Virus VaccineHumoral ImmunitiesImageImmobilizationImmuneImmune responseImmunologic AdjuvantsImmunologyIn VitroInfectionInnate Immune ResponseInvestigationLicensingLigandsMemoryModelingModificationNanotechnologyPathway interactionsPeripheralReceptor ActivationReceptor SignalingRoleScaffolding ProteinSignal TransductionStimulusStructureSubunit VaccinesSurfaceT-LymphocyteTechnologyTestingToll-like receptorsVaccinationVaccine DesignVaccinesVariantViralVirus-like particleVisualizationadaptive immune responsecellular imagingclinical developmentclinically relevantcrosslinkdensitydesignenv Gene Productsexperienceflexibilityfluorescence imaginghuman modelimmune activationin vivoin vivo evaluationlink proteinlymph nodesmouse modelnanoclusternanometernanoparticlenanoparticulatenanoscaleneutralizing antibodypandemic diseaseparticlepathogenpreclinical developmentpreservationpreventresponsescaffoldsynthetic constructtooltranslational potentialultra high resolutionvaccine developmentvaccine formulation
项目摘要
PROJECT SUMMARY
Strategies to enhance antigenicity, antibody affinity maturation, and memory induction in response to subunit
vaccines are of broad relevance for the design of effective vaccines against infectious diseases, and may be
especially important for difficult-to-neutralize pathogens such as HIV. One approach to enhance the efficacy of
subunit vaccines is to formulate antigens in a multivalent, nanoparticulate form, which promotes several aspects
of humoral immunity, and most notably enhances crosslinking of B cell receptors (BCRs). This approach has
been exploited both in licensed vaccines (e.g., the HPV and HBV vaccines), and in a great variety of vaccines
in preclinical and clinical development. However, to date it remains unclear what are the ideal characteristics of
nanoparticle antigen display. In this project, we use the unique technology of scaffolded DNA origami to engineer
nanoparticles on the 10–100 nanometer scale that offer the ability to investigate the impact of scaffold size,
antigen copy number up to more than 100, antigen-BCR affinity, as well as the nanoscale spatial organization
and dimensionality of antigen presentation on BCR activation. Specifically, we test the relative importance of
these parameters on B-cell activation, which are of central importance to the development of a successful subunit
vaccines, using the germline targeting engineered outer domain of HIV-1 gp120, termed eOD-GT8, and its
variants with different affinities, as a testbed. In vitro evaluation of early B-cell signaling and pathway activation
will be characterized, and contrasted with the benchmark strongly activating 60-mer control organized on a
protein scaffold. Single-cell fluorescence imaging is used to investigate the detailed mechanism of BCR-binding
and B-cell activation based on the optimal immunogen presentation found. These constructs are then used to
test the impact of these optimal HIV DNA-NP constructs on T-cell and B-cell response in vivo using mouse
models. Taken together, our results will offer the elucidation of the optimal immunogen presentation parameters
for effective immune cell response in the development of more effective subunit vaccines, with major translational
potential for HIV and other infectious diseases.
项目总结
对亚单位反应增强抗原性、抗体亲和力成熟和记忆诱导的策略
疫苗对于设计有效的传染病疫苗具有广泛的相关性,并可能
对艾滋病毒等难以中和的病原体尤其重要。提高药效的一种方法
亚单位疫苗是以多价、纳米颗粒的形式形成抗原,这促进了几个方面
增强体液免疫,最显著的是增强B细胞受体(BCR)的交联性。这种方法具有
在获得许可的疫苗(例如,HPV和乙肝疫苗)和各种疫苗中都得到了利用
在临床前和临床开发方面。然而,到目前为止,人们仍然不清楚什么是理想的特征
纳米颗粒抗原展示。在这个项目中,我们使用了独特的支架DNA折纸技术来工程
10-100纳米尺度的纳米颗粒,能够研究支架尺寸的影响,
抗原拷贝数高达100多个,抗原与bcr亲和力强,以及纳米尺度的空间组织
BCR活化的抗原提呈维度。具体地说,我们测试了
这些关于B细胞激活的参数,对于成功的亚单位的发展是至关重要的
使用种系靶向HIV-1 gp120工程外区的疫苗,称为EOD-GT8,及其
不同亲和力的变种,如试验床。早期B细胞信号转导和通路激活的体外研究
将被描述为特征,并与组织在
蛋白质支架。用单细胞荧光成像技术研究BCR结合的详细机制
以及基于找到的最佳免疫原提呈物激活B细胞。然后使用这些构造来
用小鼠体内检测这些优化的HIV DNA-NP结构对T细胞和B细胞应答的影响
模特们。综上所述,我们的结果将为最佳免疫原呈递参数的阐明提供依据。
在开发更有效的亚单位疫苗中进行有效的免疫细胞反应,主要是翻译
有可能感染艾滋病毒和其他传染病。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Functionalizing DNA origami to investigate and interact with biological systems.
功能化DNA折纸以研究和与生物系统相互作用。
- DOI:10.1038/s41578-022-00517-x
- 发表时间:2023-02
- 期刊:
- 影响因子:0
- 作者:
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Mark Bathe其他文献
Mark Bathe的其他文献
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{{ truncateString('Mark Bathe', 18)}}的其他基金
Investigation of the Synaptic Molecular Network using Multiplexed Imaging
使用多重成像研究突触分子网络
- 批准号:
10651858 - 财政年份:2022
- 资助金额:
$ 38.78万 - 项目类别:
Investigation of the Synaptic Molecular Network using Multiplexed Imaging
使用多重成像研究突触分子网络
- 批准号:
10510057 - 财政年份:2022
- 资助金额:
$ 38.78万 - 项目类别:
Investigation of Synthetic DNA-based Viral Particles for Spatially Controlled Antigen Presentation
基于 DNA 的合成病毒颗粒空间控制抗原呈递的研究
- 批准号:
10253355 - 财政年份:2021
- 资助金额:
$ 38.78万 - 项目类别:
Investigation of Synthetic DNA-based Viral Particles for Spatially Controlled Antigen Presentation
基于 DNA 的合成病毒颗粒空间控制抗原呈递的研究
- 批准号:
10460559 - 财政年份:2021
- 资助金额:
$ 38.78万 - 项目类别:
Structured DNA Nanoparticles Therapeutic mRNA and CRISPR/Cas9 Delivery
结构化 DNA 纳米颗粒治疗性 mRNA 和 CRISPR/Cas9 传递
- 批准号:
9762942 - 财政年份:2018
- 资助金额:
$ 38.78万 - 项目类别:
Simultaneous multiplexed in situ fluorescence imaging of neuronal proteins and messenger RNAs
神经元蛋白和信使 RNA 的同步多重原位荧光成像
- 批准号:
9289191 - 财政年份:2017
- 资助金额:
$ 38.78万 - 项目类别:
Simultaneous multiplexed in situ fluorescence imaging of neuronal proteins and messenger RNAs
神经元蛋白和信使 RNA 的同步多重原位荧光成像
- 批准号:
9889813 - 财政年份:2017
- 资助金额:
$ 38.78万 - 项目类别:
Ultra-Multiplexed Nanoscale In Situ Proteomics for Understanding Synapse Types
用于了解突触类型的超多重纳米级原位蛋白质组学
- 批准号:
9108440 - 财政年份:2014
- 资助金额:
$ 38.78万 - 项目类别:
Ultra-Multiplexed Nanoscale In Situ Proteomics for Understanding Synapse Types
用于了解突触类型的超多重纳米级原位蛋白质组学
- 批准号:
8822389 - 财政年份:2014
- 资助金额:
$ 38.78万 - 项目类别:
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