Modeling early SARS-CoV-2 pathogenesis in human lung organoids and slice cultures
Modeling early SARS-CoV-2 pathogenesis in human lung organoids and slice cultures
批准号:
10557881
负责人:
Arjun Rustagi
金额:
$19.33万
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
项目状态:
未结题
起止时间:
2022-02-01 至 2026-01-31
关键词:
2019-nCoV3-DimensionalAcuteAcute respiratory infectionAdvisory CommitteesAirAlveolar CellAlveolar MacrophagesAnimalsAutoantibodiesAutomobile DrivingBasal CellBiologyCOVID-19COVID-19 pandemicCOVID-19 pathogenesisCOVID-19 patientCell CommunicationCell LineCellsCessation of lifeCommunicable DiseasesDataDependenceDevelopmentDevelopment PlansDiseaseEnvironmentEpithelial CellsEpitheliumEventFlow CytometryFundingGene ExpressionGenesGoalsHumanIL18 geneImmuneImmune responseImmunityImmunologyIn VitroInfectionInflammationInflammatoryInflammatory ResponseInnate Immune ResponseInterferon Type IInterferonsInterleukin-6KnowledgeLiquid substanceLungLung diseasesMacrophageMacrophage ActivationManuscriptsMapsMentorsMicroscopyModelingMucous MembraneMutationOrganoidsPathogenesisPathogenicityPathway interactionsPatientsPhysiciansPlayPositioning AttributeProcessProductivityProtein AnalysisQuantitative Reverse Transcriptase PCRRNA amplificationResearchResourcesRestRoleSARS-CoV-2 infectionSARS-CoV-2 pathogenesisSARS-CoV-2 variantSamplingScientistSignal TransductionSliceStimulusStructure of parenchyma of lungSupporting CellSystemTNF geneTechniquesTestingTherapeutic InterventionTrainingTranscriptTropismUniversitiesVariantViralViral PathogenesisViral ProteinsVirusVirus ReplicationWorkacute infectioncareercareer developmentcell typecombatcytokinedesignglobal healthhigh riskimmune activationimmune cell infiltratein vivoinnate immune pathwaysinsightinstructornasopharyngeal swabnovelnovel diagnosticsnovel therapeutic interventionnovel therapeuticspandemic diseaseprogramsprotein expressionremdesivirrespiratoryrespiratory pathogenrespiratory virusresponsesevere COVID-19single cell analysissingle-cell RNA sequencingstatisticsstem cellssuccesstargeted treatmenttoolvaccine deliveryvaccine hesitancyvariant of interestvariants of concern
中文摘要
项目摘要
COVID-19仍然是一场持续的全球健康危机,部分原因是新出现的变种。基本问题
关于SARS-CoV-2感染驱动下肺炎症的机制,
由于缺乏体外感染模型。更好地理解变异生物学和免疫途径
参与早期SARS-CoV-2感染可能为开发新的治疗策略提供见解。
抗病毒细胞因子I型干扰素及其下游效应与COVID-19有关。
SARS-CoV-2可能抑制或促进肺中某些细胞类型的干扰素效应,
病毒变种之间的联系我的初步工作表明,类器官和肺切片培养可用于研究
这些早期事件在SARS-CoV-2感染,并确定巨噬细胞作为一种细胞类型,激活
干扰素途径感染的文化。因此,我建议使用定量PCR,单细胞RNA测序,
和流式细胞术来研究病毒变体,并深入分析病毒和宿主基因和蛋白的变化
感染时的表达。我将研究高度相关的细胞类型,它们可以以类似的方式相互作用,
在体内肺的方式。我将研究干扰素刺激的基因反应,并确定细胞类型,
其被调节或将是治疗干预的良好靶点。这些知识将至关重要
我们抗击COVID-19疫情的努力。
我目前是斯坦福大学传染病系凯瑟琳·布利什博士实验室的研究员
我正在被提升为全职教练。斯坦福大学提供了一个
杰出的科学环境,在那里所有必要的资源,这个项目的成功,
我的长期目标是成为一名独立的物理学家,科学家,研究重点是
呼吸道病毒发病机制我的目标是建立一个研究计划,重点是建立模型,
新出现的原发性肺组织感染,目的是开发新的治疗方法。
为了实现这一目标,我设计了一个量身定制的职业发展计划,
非正式培训。这次培训将增强我在肺生物学、免疫学和测序方面的专业知识
分析.这些主题的非正式培训将由我的导师凯瑟琳·布利什博士和其他人提供。
我的顾问委员会,卡尔文郭博士,马克·克拉斯诺博士,苏珊·霍姆斯博士和本·平斯基博士。与他们的
指导,我将完成拟议的项目,提交研究手稿,获得进一步的资金,并获得
独立的研究职位。
英文摘要
PROJECT SUMMARY
COVID-19 remains an ongoing global health crisis, in part due to emerging variants. Fundamental questions
remain about the mechanisms by which SARS-CoV-2 infection drives inflammation in the lower lung, in part
due to the lack of in vitro infection models. Better understanding of variant biology and the immune pathways
involved in early SARS-CoV-2 infection could offer insights for the development of novel therapeutic strategies.
The antiviral cytokines type I interferons and their downstream effects have been implicated in COVID-19.
SARS-CoV-2 may inhibit or promote interferon effects in some cell types in the lung, and this may differ
between viral variants. My preliminary work shows that organoids and lung slice cultures can be used to study
these early events in SARS-CoV-2 infection and identifies macrophages as a cell type that activates the
interferon pathway in infected cultures. Thus, I propose using quantitative PCR, single-cell RNA sequencing,
and flow cytometry to study viral variants and to deeply profile the changes to viral and host gene and protein
expression during infection. I will study highly relevant cell types that can interact with each other in a similar
fashion to the in vivo lung. I will study the interferon stimulated gene response and identify the cell types in
which it is being modulated or would be good targets for therapeutic intervention. This knowledge will be critical
to our efforts to combat the COVID-19 pandemic.
I am currently a fellow in Dr. Catherine Blish’s lab in the Division of Infectious Diseases at Stanford University
and I am in the process of being promoted to a full time Instructor position. Stanford University offers an
outstanding scientific environment, where all the resources necessary to the success of this project are made
available to me. My long-term goal is to become an independent physician-scientist, with a research focus in
respiratory viral pathogenesis. I aim to establish a research program focused on modeling established and
emerging infections in primary lung tissue with a goal of developing new treatments.
To achieve this goal, I have designed a tailored career development plan that comprises both formal and
informal training. This training will enhance my expertise in lung biology, immunology, and sequencing
analysis. Informal training in these topics will be provided by my mentor, Dr. Catherine Blish, and by the rest of
my advisory committee, Dr. Calvin Kuo, Dr. Mark Krasnow, Dr. Susan Holmes, and Dr. Ben Pinsky. With their
guidance, I will complete the proposed project, submit research manuscripts, obtain further funding, and obtain
an independent research position.
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会议论文
Modeling early SARS-CoV-2 pathogenesis in human lung organoids and slice cultures
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批准号:10449059
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项目类别:
-
资助金额:$19.33万
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财政年份:2022
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负责人:Arjun Rustagi
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依托单位:
海外基金