Functional dynamics of TB granuloma architecture
结核肉芽肿结构的功能动力学
基本信息
- 批准号:10593978
- 负责人:
- 金额:$ 61.57万
- 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:2022-03-18 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:Animal ModelAppearanceArchitectureBiologyCell CommunicationCellsCharacteristicsChronicClinicalCollaborationsComplementDataData AnalysesDissociationEnvironmentFailureFlow CytometryForce of GravityFundingGoalsGranulomaGranuloma by SiteHumanHuman PathologyImageImmuneImmunityImmunologicsImmunologyInfectionInfection ControlInterferon Type IInterferon Type IIIntramural Research ProgramKnowledgeLabelLocationLymphocyteMacaca mulattaMacrophageModificationMolecularMouse StrainsMovementMusMycobacterium tuberculosisMyeloid CellsNational Institute of Allergy and Infectious DiseaseNatureNecrosisOutcomePathogenesisPathologicPersonsPopulationPopulation DynamicsPositioning AttributePreventionResearch PersonnelResourcesRoleSamplingSignal TransductionSiteSourceStructureSystemTestingTimeTissuesTreatment outcomeTuberculosisUniversitiesVirulenceWagesWorkdata integrationhuman datahuman tissueimprovedinsightlatent infectionlive cell imaginglung injurylung repairmultidimensional datapathogenrecruitresponsespatial relationshipsuccesssynergismtherapy developmenttraffickingtranscriptomicstuberculosis granulomatuberculosis treatment
项目摘要
Project Summary/Abstract
Understanding and eliminating TB depends on understanding the host and pathogen dynamics in granulomas,
where the outcomes of M. tuberculosis infection are determined. Despite substantial efforts, the cellular
composition, spatial interactions, and mechanisms that determine outcomes such as pathologic
granuloma necrosis are poorly understood. One explanation for the limited understanding of granulomas is that
most studies are performed in a single experimental system in isolation. We have formed a consortium to
perform and integrate studies of TB granulomas in three systems: humans, rhesus macaques, and new
strains of mice. In these three systems, we will address several major questions in TB granuloma biology:
what is the extent of diversity in cell composition in TB granulomas? What regulates cell trafficking and
spatial interactions in TB granulomas? What are the roles of type I interferons (TIIFN) and interferon
gamma (IFNg) in regulating and determining cell trafficking, differentiation, spatial relationships, and activation
states in TB granulomas? What are the pathogen and host determinants of necrosis, a pathologic outcome,
in TB granulomas? Our primary mode for investigating these and other questions will be high-parameter
multiplex immunostaining of TB granulomas from the three species, as this will provide essential insight into
the spatial relationships between immune cell subsets. Multiplex immunostaining will be complemented by
studies of live imaging of cell dynamics in rhesus macaque granulomas and by strategically-timed transfers
of labeled cells in rhesus macaques and diverse strains of mice. The value of the multiplex immunostaining
studies will be further enhanced by deep characterization of dissociated cell populations at the single-cell
level, using high parameter flow cytometry and single-cell transcriptomics. A uniquely important contribution
of our proposed project is the computational integration of data from humans, rhesus macaques, and new
strains of mice. By integrating multispecies data, we will identify the features of TB granulomas that are
common to all three species, and we will identify factors that are unique to granulomas in each species, to
guide further modifications to improve the utility of studies in animal models. Integration of the data from the
three species will allow studies in rhesus macaques to be compared with those of human samples and
new strains of mice; this will improve the understanding and interpretation of human pathology studies, and
enhance the value of studies that can take advantage of using the unique advantages of mice for mechanistic
studies. Together, our studies will advance the knowledge and understanding of TB biology, and guide
development of interventions to improve treatment outcomes, limit lung damage, and improve lung tissue
repair in people suffering from TB.
项目摘要/摘要
了解和消除结核病取决于了解肉芽肿中宿主和病原体的动态,
决定结核分枝杆菌感染结果的地方。尽管付出了巨大的努力,但蜂窝
组成、空间相互作用和决定结果的机制,如病理
肉芽肿坏死知之甚少。对肉芽肿认识有限的一种解释是
大多数研究都是在一个单独的实验系统中孤立进行的。我们已经组成了一个财团来
在三个系统中执行和整合对结核肉芽肿的研究:人类、猕猴和新的
不同品系的老鼠。在这三个系统中,我们将解决结核病肉芽肿生物学中的几个主要问题:
结核肉芽肿细胞成分的多样性有多大?是什么规范了细胞贩运和
结核肉芽肿的空间相互作用?I型干扰素和干扰素的作用是什么?
伽玛(IFNG)在调节和确定细胞运输、分化、空间关系和激活中的作用
结核病肉芽肿的状态?什么是坏死的病原体和宿主决定因素,病理结果,
在肺结核肉芽肿中?我们调查这些问题和其他问题的主要模式将是高参数
这三个物种的结核肉芽肿的多重免疫染色,因为这将提供基本的洞察
免疫细胞亚群之间的空间关系。多重免疫染色将得到以下补充
恒河猴肉芽肿细胞动力学的实时成像研究
在恒河猴和不同品系的小鼠中标记细胞的数量。多重免疫染色的临床应用价值
通过对单细胞分离的细胞群体的深入表征,研究将得到进一步加强
水平,采用高参数流式细胞术和单细胞转录组。独一无二的重要贡献
我们提议的项目是对来自人类、恒河猴和新的
不同品系的老鼠。通过整合多物种数据,我们将确定结核肉芽肿的特征
这三种肉芽肿都有共同之处,我们将找出每种肉芽肿特有的因素,以
指导进一步修改,以提高动物模型研究的实用性。集成来自
三个物种将允许对恒河猴的研究与人类样本进行比较,并
新的小鼠品系;这将提高对人类病理学研究的理解和解释,以及
提高可以利用鼠标的独特优势进行机械研究的价值
学习。我们的研究将共同促进对结核病生物学的了解和理解,并指导
发展干预措施以改善治疗结果、限制肺损伤和改善肺组织
对患有结核病的人进行修复。
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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Joel D. Ernst其他文献
The immunological life cycle of tuberculosis
结核病的免疫生命周期
- DOI:
10.1038/nri3259 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:60.900
- 作者:
Joel D. Ernst - 通讯作者:
Joel D. Ernst
Transfer of phagocytosed particles to the parasitophorous vacuole of Leishmania mexicana is a transient phenomenon preceding the acquisition of annexin I by the phagosome.
吞噬颗粒向墨西哥利什曼原虫寄生液泡的转移是吞噬体获得膜联蛋白 I 之前的短暂现象。
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:4
- 作者:
Helen L. Collins;Ulrich E. Schaible;Joel D. Ernst;David G. Russell - 通讯作者:
David G. Russell
Editorial response: variation in clinical and immune responses to bacille Calmette-Guérin--implications for an improved tuberculosis vaccine.
编辑回应:卡介苗临床和免疫反应的变化——对改进结核病疫苗的影响。
- DOI:
10.1086/515202 - 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Joel D. Ernst - 通讯作者:
Joel D. Ernst
Antibody-Fab and -Fc features promote emMycobacterium tuberculosis/em restriction
抗体的 Fab 和 Fc 特征促进了对结核分枝杆菌的限制。
- DOI:
10.1016/j.immuni.2025.05.004 - 发表时间:
2025-06-10 - 期刊:
- 影响因子:26.300
- 作者:
Patricia S. Grace;Joshua M. Peters;Jaimie Sixsmith;Richard Lu;Edward B. Irvine;Corinne Luedeman;Brooke A. Fenderson;Andrew Vickers;Matthew D. Slein;Tanya McKitrick;Mo-Hui Wei;Richard D. Cummings;Aaron Wallace;Lisa A. Cavacini;Alok Choudhary;Megan K. Proulx;Christopher Sundling;Gunilla Källenius;Rajko Reljic;Joel D. Ernst;Galit Alter - 通讯作者:
Galit Alter
Finding and filling the knowledge gaps in mechanisms of T cell-mediated TB immunity to inform vaccine design
寻找并填补 T 细胞介导的结核病免疫机制中的知识空白,为疫苗设计提供信息
- DOI:
10.1038/s41577-025-01192-z - 发表时间:
2025-06-13 - 期刊:
- 影响因子:60.900
- 作者:
Emma Lefrançais;Denis Hudrisier;Olivier Neyrolles;Samuel M. Behar;Joel D. Ernst - 通讯作者:
Joel D. Ernst
Joel D. Ernst的其他文献
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{{ truncateString('Joel D. Ernst', 18)}}的其他基金
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens
功能独特的人类 CD4 T 细胞对新型进化选择的结核分枝杆菌抗原的反应
- 批准号:
10735075 - 财政年份:2023
- 资助金额:
$ 61.57万 - 项目类别:
Functional dynamics of TB granuloma architecture
结核肉芽肿结构的功能动力学
- 批准号:
10358264 - 财政年份:2022
- 资助金额:
$ 61.57万 - 项目类别:
Host genetic diversity, mononuclear phagocytes, and outcomes of TB
宿主遗传多样性、单核吞噬细胞和结核病的结果
- 批准号:
10005738 - 财政年份:2020
- 资助金额:
$ 61.57万 - 项目类别:
Host genetic diversity, mononuclear phagocytes, and outcomes of TB
宿主遗传多样性、单核吞噬细胞和结核病的结果
- 批准号:
10194362 - 财政年份:2020
- 资助金额:
$ 61.57万 - 项目类别:
Antigen export in M. tuberculosis evasion of CD4 T cells
结核分枝杆菌逃避 CD4 T 细胞的抗原输出
- 批准号:
9318402 - 财政年份:2016
- 资助金额:
$ 61.57万 - 项目类别:
Epitope-specific T cell activation to complement TB immunity and vaccine efficacy
表位特异性 T 细胞激活可补充结核病免疫和疫苗功效
- 批准号:
8867688 - 财政年份:2014
- 资助金额:
$ 61.57万 - 项目类别:
Initiation of the Immune Response to M. tuberculosis
对结核分枝杆菌的免疫反应的启动
- 批准号:
8678398 - 财政年份:2014
- 资助金额:
$ 61.57万 - 项目类别:
Mycobacterium tuberculosis evasion of CD4+ T cells in vivo
体内结核分枝杆菌逃避 CD4 T 细胞
- 批准号:
8678383 - 财政年份:2013
- 资助金额:
$ 61.57万 - 项目类别:
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