Functional dynamics of TB granuloma architecture

结核肉芽肿结构的功能动力学

• 批准号: 10593978
• 负责人: Joel D. Ernst
• 金额: $ 61.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10593978
• 关键词: Animal Model; Appearance; Architecture; Biology; Cell Communication; Cells; Characteristics; Chronic; Clinical; Collaborations; Complement; Data; Data Analyses; Dissociation; Environment; Failure; Flow Cytometry; Force of Gravity; Funding; Goals; Granuloma; Granuloma by Site; Human; Human Pathology; Image; Immune; Immunity; Immunologics; Immunology; Infection; Infection Control; Interferon Type I; Interferon Type II; Intramural Research Program; Knowledge; Label; Location; Lymphocyte; Macaca mulatta; Macrophage; Modification; Molecular; Mouse Strains; Movement; Mus; Mycobacterium tuberculosis; Myeloid Cells; National Institute of Allergy and Infectious Disease; Nature; Necrosis; Outcome; Pathogenesis; Pathologic; Persons; Population; Population Dynamics; Positioning Attribute; Prevention; Research Personnel; Resources; Role; Sampling; Signal Transduction; Site; Source; Structure; System; Testing; Time; Tissues; Treatment outcome; Tuberculosis; Universities; Virulence; Wages; Work; data integration; human data; human tissue; improved; insight; latent infection; live cell imaging; lung injury; lung repair; multidimensional data; pathogen; recruit; response; spatial relationship; success; synergism; therapy development; trafficking; transcriptomics; tuberculosis granuloma; tuberculosis treatment

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 理解和消除结核病取决于理解颗粒中的宿主和病原体动力学， 确定结核分枝杆菌感染的结果。尽管做出了巨大的努力，但 组成，空间相互作用和确定诸如病理等结果的机制 肉芽肿坏死知之甚少。对肉芽瘤有限理解的一种解释是 大多数研究是在单个实验系统中进行的。我们已经组建了一个财团 在三个系统中执行和整合TB肉芽肿的研究：人类，恒河猕猴和新的 小鼠菌株。在这三个系统中，我们将解决结核病生物学的几个主要问题： TB肉芽肿的细胞组成多样性的程度是多少？是什么调节细胞贩运和 结核病肉芽肿的空间相互作用？ I型干扰素（TIIFN）和干扰素的角色是什么 伽玛（IFNG）在调节和确定细胞运输，分化，空间关系和激活方面 结核病肉芽肿的状态？坏死的病原体和宿主决定因素是什么，一种病理学结果， 在结核病肉芽肿？我们调查这些问题和其他问题的主要模式将是高参数 TB肉芽肿来自这三个物种的多重免疫染色，因为这将提供对 免疫细胞亚群之间的空间关系。多重免疫染色将由 恒河猕猴颗粒中细胞动力学的实时成像和通过战略性接收的研究 恒河猕猴和小鼠菌株中标记的细胞的标记细胞。多重免疫染色的值 通过对单细胞分离的细胞种群的深刻表征，将进一步增强研究 级别，使用高参数流式细胞仪和单细胞转录组学。独特的重要贡献 我们拟议的项目是来自人类，恒河猴和新的数据的计算集成 小鼠菌株。通过集成多物种数据，我们将确定TB肉芽肿的特征 这三种物种共有，我们将确定每个物种中颗粒瘤所独有的因素 指导进一步的修改以改善动物模型研究的效用。从 将三种物种允许在恒河猕猴中进行研究，并将其与人类样本的研究进行比较 新小鼠菌株；这将改善对人类病理学研究的理解和解释，并 增强可以利用小鼠的独特优势进行机械优势的研究价值 研究。我们的研究将共同​​提高对结核病生物学的知识和理解，并指导 开发干预措施以改善治疗结果，限制肺损伤并改善肺组织 对患有结核病的人进行维修。