A multi-scale and multi-system approach to understand granuloma formation in TB

了解结核病肉芽肿形成的多尺度、多系统方法

• 批准号: 7499451
• 负责人: Denise E Kirschner
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499451
• 关键词: Address; Animal Model; Animals; Antibiotics; Antigen Presentation; Antigens; Area; Arts; Automobile Driving; Binding; Biological; Blood Circulation; Breathing; Cell Communication; Cells; Cessation of life; Chemicals; Collaborations; Collection; Communicable Diseases; Communities; Computer Simulation; Data; Dendritic Cells; Development; Disease; Disease Outcome; Doctor of Philosophy; Effector Cell; Environment; Equipment; Evaluation; Event; Funding; Genus Mycobacterium; Goals; Grant; Granuloma; Human Resources; Immune; Immune response; Immunity; Immunology; Individual; Infection; Infection Control; Integration Host Factors; Lead; Leadership; Link; Lung; Lymph; Maintenance; Manuscripts; Mentors; Michigan; Microbiology; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Organ; Outcome; Persons; Postdoctoral Fellow; Privacy; Process; Publications; Purpose; RNA Interference; Recruitment Activity; Research Personnel; Research Project Grants; Resources; Role; Running; Signal Transduction; Structure; Students; System; Systems Biology; T-Lymphocyte; Testing; Time; TimeLine; Tissues; Travel; Tuberculosis; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Uncertainty; Universities; Vaccine Therapy; Videoconferences; Videoconferencing; Wages; Work; World Health; abstracting; base; chemokine; cytokine; day; human TNF protein; in vivo; interdisciplinary approach; interdisciplinary collaboration; latent infection; lymph nodes; mathematical model; member; molecular scale; multi-scale modeling; nonhuman primate; outreach; pulmonary granuloma; receptor; success; tool; trafficking; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): Tuberculosis is responsible for 2 million deaths per year. The interplay between host and bacterial factors leads to different disease outcomes (latency, primary tuberculosis, reactivation tuberculosis). A key outcome is the formation of a collection of immune cells termed the granuloma. This structure acts not only as an immune microenvironment and a barrier to dissemination but also as a niche for long-term bacterial survival. The long- term goal of this project is to identify factors that contribute to different outcomes of M. tuberculosis infection. We hypothesize that these different infection outcomes are reflected locally at the level of the granuloma and that granuloma structure is the result of the interplay of events at organ, tissue, cellular, and molecular scales over the time course of minutes to years. Several models of granuloma formation in tuberculosis will be integrated: pulmonary granulomas induced by M. tuberculosis antigen (PPD) coated beads in vivo, M. tuberculosis infection in mice and non-human primates, and multi-scale in silico models. Our studies will include multiple spatial and temporal scales to address the following aims. Aim 1: Determine how specific immune cells and effector molecules in the lung influence the formation of different granuloma structures. Aim 2: Determine the role of dendritic cell and T cell trafficking between lung granuloma and draining lymph nodes in influencing granuloma development. Aim 3: Identify the mechanisms that determine TNF availability for the purpose of understanding how granulomas form as well as how treatment with anti-TNF-therapies leads to TB reactivation. Our interdisciplinary team's approach for integrating data and in silico models over the relevant biological and temporal scales will allow us to predict and test hypotheses regarding key factors that influence granuloma formation and structure. These factors are likely central to determining different disease outcomes following M. tuberculosis infection and will provide a new tool for testing therapies and vaccines against M. tuberculosis. Tuberculosis (TB) is a world health issue. The immune response to TB is unique, resulting in the formation of structures called granulomas in the lungs of infected people. We seek to understand the formation and function of these structures using integrated data generated from a variety of animal and computational models. (End of Abstract)

描述（由申请人提供）：结核病每年造成200万人死亡。宿主和细菌因子之间的相互作用导致不同的疾病结局（潜伏期，原发性结核病，重新激活结核病）。一个关键的结果是形成了称为肉芽肿的免疫细胞的集合。这种结构不仅充当免疫微环境和传播的障碍，而且还充当了长期细菌生存的利基市场。该项目的长期目标是确定导致结核分枝杆菌感染不同结果的因素。我们假设这些不同的感染结果在肉芽肿的水平上反映在局部反映，并且肉芽瘤结构是在几分钟到几年的时间过程中器官，组织，组织，细胞和分子尺度上事件相互作用的结果。结核病中肉芽肿形成的几种模型将整合：结核分枝杆菌抗原（PPD）在体内涂有珠的肺肉芽肿，在体内涂有珠的珠子，小鼠和非人类灵长类动物的结核分枝杆菌感染，以及在硅胶模型中多尺度。我们的研究将包括多个空间和时间尺度，以解决以下目标。目标1：确定肺中特定的免疫细胞和效应分子如何影响不同的肉芽肿结构的形成。 AIM 2：确定肺肉芽肿和排干淋巴结之间树突状细胞和T细胞运输在影响肉芽肿发育中的作用。 AIM 3：确定确定TNF可用性的机制，以了解肉芽肿如何形成以及如何用抗TNF触及治疗的治疗导致TB重新激活。我们跨学科团队在相关的生物学和时间尺度上整合数据和计算机模型中的方法将使我们能够预测和检验有关影响颗粒瘤形成和结构的关键因素的假设。这些因素可能是结核分枝杆菌感染后确定不同疾病结果的核心，​​并将为针对结核分枝杆菌的疗法提供新的工具。结核病（TB）是世界健康问题。对结核病的免疫反应是独一无二的，导致在感染者的肺中形成称为肉芽肿的结构。我们试图使用从各种动物和计算模型产生的集成数据来理解这些结构的形成和功能。 （抽象的结尾）