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 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。