Modeling granuloma formation using engineered microcapsules

使用工程微胶囊模拟肉芽肿形成

• 批准号: 9016189
• 负责人: ROBERT L MODLIN
• 金额: $ 22.74万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9016189
• 关键词: Antigen Presentation; Autocrine Communication; Biomedical Engineering; Cell Communication; Cell physiology; Cells; Cellular Immunology; Chronic; Collaborations; Collection; Communicable Diseases; Complex; Data; Encapsulated; Engineering; Extracellular Matrix; Gel; Generations; Geometry; Giant Cells; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granuloma; Heparin; Heparin Binding; Host Defense; Host Defense Mechanism; Human; Immune; Immune response; Immune system; In Vitro; Infection; Infectious Agent; Infectious granuloma; Interleukin-10; Interleukin-15; Investigation; Laboratories; Lepromatous Leprosy; Leprosy; Lesion; Ligands; Lipids; Lipoproteins; Mediating; Microbe; Microcapsules drug delivery system; Microfluidics; Modeling; Mycobacterium leprae; Natural Immunity; Phagocytosis; Population; Porosity; Proteins; Protocols documentation; Role; Site; T-Lymphocyte; TLR2 gene; Technology; Testing; Therapeutic Intervention; TimeLine; Tissues; Tuberculoid leprosy; antimicrobial; capsule; combat; copolymer; cytokine; design; ethylene glycol; immune function; in vivo; insight; macrophage; microbial; novel; novel strategies; particle; pathogen; programs; public health relevance; research study; tool

 DESCRIPTION (provided by applicant): The long term objective of this proposal is to gain insight into mechanisms of host defense against infectious agents in humans, through the study of leprosy as a model. At the site of infection, organized collections of macrophages form granulomas to defend against the pathogen, Mycobacterium leprae. Our goal is to understand mechanisms of granuloma formation and function in human infectious disease. We will test the hypothesis that distinct subsets of macrophages regulate granuloma formation, and hence host defense. This will be accomplished by using bioengineered 3D microconstructs to encapsulate and confine MΦ, facilitating immune cell interaction, replicating the in vivo tissue microenvironment where granulomas form. Our aims are: 1) Fabricate artificial granulomas using droplet microfluidics to model human leprosy infection, and, 2) Investigate the role of macrophage subsets in granuloma formation and function. In addition we will study the function of Langhans multinucleated giant cells, a hallmark of host defense in chronic infection. Together these aims target an integrated understanding of the interaction between a microbial pathogen and host-derived MΦ, with the goal to uncover novel mechanisms of immune responses that contain the pathogen, which might serve as targets host-directed therapies to modulate the immune response in human infectious disease. As such, this project brings together two laboratories, the Modlin lab with expertise in cellular immunology and the Revzin lab with expertise in bioengineering microstructures to optimize cell-cell interactions, to develop a new approach to study mechanisms by which granulomas are formed and contribute to host defense in humans.

 描述（由申请人提供）：该提案的长期目标是通过研究麻风病作为模型，深入了解宿主针对人类感染因子的防御机制。在感染部位，有组织的巨噬细胞集合形成肉芽肿。为了防御病原体麻风分枝杆菌，我们的目标是了解人类传染病中肉芽肿形成和功能的机制，我们将检验巨噬细胞的不同亚群调节肉芽肿形成的假设。这将通过使用生物工程 3D 微结构来封装和限制 MΦ、促进免疫细胞相互作用、复制肉芽肿形成的体内组织微环境来实现。我们的目标是：1) 使用液滴微流控技术制造人工肉芽肿来模拟人类麻风病。感染，以及，2) 研究巨噬细胞亚群在肉芽肿形成和功能中的作用。此外，我们将研究 Langhans 的功能。多核巨细胞是慢性感染中宿主防御的一个标志，这些目标共同致力于对微生物病原体和宿主来源的 MΦ 之间的相互作用进行综合理解，以揭示包含病原体的免疫反应的新机制，这可能是一个新的机制。作为靶向宿主导向疗法来调节人类传染病的免疫反应，因此，该项目汇集了两个实验室，即拥有细胞免疫学专业知识的 Modlin 实验室和拥有生物工程微观结构专业知识的 Revzin 实验室，以进行优化。细胞与细胞之间的相互作用，开发一种新方法来研究肉芽肿形成并有助于人类宿主防御的机制。