Modeling granuloma formation using engineered microcapsules

 描述（由申请方提供）：本提案的长期目标是通过以麻风病为模型的研究，深入了解宿主对人类传染性病原体的防御机制。在感染部位，有组织的巨噬细胞聚集形成肉芽肿，以抵御病原体麻风分枝杆菌。我们的目标是了解肉芽肿的形成机制和功能在人类感染性疾病。我们将检验巨噬细胞的不同亚群调节肉芽肿形成，从而调节宿主防御的假设。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）使用液滴微流体制造人工肉芽肿以模拟人类麻风病感染，和2）研究巨噬细胞亚群在肉芽肿形成和功能中的作用。此外，我们将研究朗汉斯多核巨细胞的功能，这是慢性感染中宿主防御的标志。这些目标共同针对微生物病原体和宿主来源的MΦ之间的相互作用的综合理解，目标是揭示包含病原体的免疫应答的新机制，其可能作为靶向宿主的治疗以调节人类感染性疾病中的免疫应答。因此，该项目汇集了两个实验室，具有细胞免疫学专业知识的Modlin实验室和具有生物工程微观结构专业知识的Revzin实验室，以优化细胞-细胞相互作用，开发一种新的方法来研究肉芽肿形成的机制，并有助于人类的宿主防御。

 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.