An Integrated In Vitro 3D Model of Human Bone Marrow and Peripheral Infection

人体骨髓和外周感染的集成体外 3D 模型

• 批准号: 10223815
• 负责人: Steven CARL George
• 金额: $ 64.11万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10223815
• 关键词: Address; Antibiotic Resistance; Antibiotics; Back; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Beds; Biological; Biological Models; Biology; Blood Circulation; Blood Vessels; Bone Marrow; Cells; Collaborations; Communication; Detection; Emergency Situation; Endothelium; Extramedullary; Feedback; Fibroblasts; Goals; Gram-Positive Bacteria; Hematopoiesis; Hematopoietic stem cells; Home; Homeostasis; Host Defense; Human; Immune response; Immune system; Immunology; Immunotherapy; In Vitro; Infection; Infectious Agent; Infectious Skin Diseases; Innate Immune Response; Innate Immune System; Leukocytes; Link; Marrow; Mediator of activation protein; Methicillin Resistance; Microfluidics; Modeling; Molecular; Mus; Myelogenous; Nature; Osteomyelitis; Pathogenicity; Patients; Pattern; Peripheral; Play; Process; Production; Research Personnel; Risk; Signal Transduction; Site; Skin; Skin wound healing; Sterility; Technology; Testing; Time; Tissues; Virulence Factors; Virulent; antibiotic resistant infections; antimicrobial; bacterial resistance; base; combat; design; experience; human model; in vitro Model; innate immune mechanisms; keratinocyte; macrophage; mouse model; neutrophil; new technology; novel; novel therapeutics; organ on a chip; pathogen; recruit; residence; response; three dimensional cell culture; three-dimensional modeling; tissue culture; trafficking

PROJECT SUMMARY The immune response to a peripheral infection is a fundamental feature of the human immune system, providing robust protection from a myriad of infectious agents. The response necessarily invokes the innate immune system, but many features of this orchestrated response are poorly understood, limiting our ability to augment the response to new and ever evolving threats. In particular, the innate response engages the bone marrow to modify the magnitude and dynamics of the response. There are important differences between the mouse (primary model to study the innate immune response) and human innate immune responses, in particular scale and dynamics, and new technologies in 3D cell and tissue culture provide exciting opportunities in the field known as “organ-on-a-chip”. The primary goal of this project is to design, build, and validate an integrated human “ImmuneChip” platform that mimics key dynamic features of the production and trafficking of polymorphonuclear leukocytes (PMN, i.e., neutrophils) between the bone marrow, systemic circulation, and peripheral site of bacterial infection. Developing this technology is important because of the alarming expansion of antibiotic resistance bacteria which will demand creative and alternative approaches to combat. The specific aims are to: 1) design, build, and test a microfluidic ImmuneChip that simulates the homeostatic interaction between bone marrow, systemic circulation, and a sterile skin model; 2) establish a homeostatic circuit in the ImmuneChip in which HSPC expansion, PMN trafficking, and antimicrobial defenses respond to soluble mediators of bacterial infection; and 3) demonstrate an appropriate response to contain a methicillin-resistant (and sensitive) S. aureus peripheral infection within the ImmuneChip, and produce a test- bed for novel biological strategies to combat infection. The in vitro model will be able to uniquely simulate the dynamics of peripheral infection-bone marrow communication including transport barriers, residence time in the circulation, and dilution due to the large difference in the size of the compartments. Accomplishing our primary goal will create a technology that advances a new class of model systems to understand the human response to peripheral infection.

项目摘要 对外周感染的免疫应答是人类免疫系统的基本特征， 从而提供对多种传染性病原体的强大保护。这种反应必然会唤起 免疫系统，但这种协调反应的许多特征知之甚少，限制了我们的能力， 加强对新的和不断演变的威胁的反应。特别是，先天反应使骨骼 骨髓来修改响应的幅度和动力学。有重要的区别之间的 小鼠（研究先天免疫应答的主要模型）和人先天免疫应答， 特定的规模和动力学，以及3D细胞和组织培养的新技术提供了令人兴奋的 在被称为“器官芯片”领域的机会。该项目的主要目标是设计、建造和 验证一个集成的人类“免疫芯片”平台，该平台模仿生产的关键动态特征， 多形核白细胞（PMN，即，中性粒细胞）之间的骨髓，全身 循环和外周部位的细菌感染。开发这项技术很重要，因为 抗生素耐药性细菌的惊人扩张，这将需要创造性和替代性的方法， 战斗具体目标是：1）设计，构建和测试微流控免疫芯片， 骨髓、体循环和无菌皮肤模型之间的稳态相互作用; 2）建立 免疫芯片中的稳态回路，其中HSPC扩增、PMN运输和抗菌防御 响应细菌感染的可溶性介质;和3）证明适当的响应，以包含 耐甲氧西林（和敏感）S.金黄色葡萄球菌外周感染内的免疫芯片，并产生一个测试- 为对抗感染的新生物策略奠定了基础。体外模型将能够独特地模拟 外周感染-骨髓通讯的动力学，包括转运屏障、在 循环和由于隔室大小的巨大差异而导致的稀释。实现我们 主要目标是创造一种技术，推动一类新的模型系统，以了解人类 对外周感染的反应。