A 3D human tissue-engineered lung model to study immune responses to Respiratory Syncytial Virus

用于研究呼吸道合胞病毒免疫反应的 3D 人体组织工程肺模型

基本信息

批准号：
10206139
负责人：
Heather Fahlenkamp
金额：
$ 51.79万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206139
关键词：
3-Dimensional Activities of Daily Living Adopted Adult Age Alveolar Macrophages Animal Model Antiviral Response Aspirate substance Biological Models Biomedical Engineering Blood Bronchiolitis Bronchoalveolar Lavage Cell Communication Cell surface Cells Child Clinical Data Communication Dendritic Cells Development Disease Distal Endothelium Engineering Environment Epithelial Cells Exhibits Experimental Models Extracellular Matrix Future Goals Homeostasis Human Immune Immune response Immunity Immunologics Infant Infection Infectious Agent Inflammatory Inflammatory Response Influenza A virus Innate Immune Response Integration Host Factors Knowledge Life Lung Lung Transplantation Lung diseases Measures Modeling Morphology Mus Myeloid Cells Neonatal Newborn Infant Outcomes Research Pathogenesis Pathology Patients Phenotype Physiological Play Population Predisposition Primary Infection Production Research Research Project Grants Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Role Source Stimulus Stromal Cells Structure of respiratory epithelium Testing Therapeutic Intervention Time Tissue Engineering Umbilical Cord Blood Vascular Endothelium Viral Viral Bronchiolitis Viral Pathogenesis Viral Pneumonia Virulence Factors Virus Diseases Work airway epithelium cell motility cell type chemokine cytokine design experience human tissue improved innate immune pathways lung basal segment macrophage monocyte neonate neutrophil novel novel therapeutics novel vaccines peripheral blood preventive intervention recruit response scaffold treatment strategy vaccine development

项目摘要

Respiratory syncytial virus (RSV) is the leading cause of viral bronchiolitis and pneumonia worldwide, infecting more than 70% of children in the first year. RSV causes more frequent and severe infections in infants compared to adults. The development of vaccines has been complicated by the fact that host immune responses to RSV play a significant role in disease pathogenesis. A key to RSV pathogenesis may lie in defining the mechanisms associated with a deficient immune response at a time of immunological immaturity. The study of the responses of lung-resident myeloid cells to RSV in human infants has been limited due to the lack of available models. While it is possible to measure cytokines and chemokines present in tracheal aspirates in RSV bronchiolitis patients, it is difficult to obtain sufficient numbers of cells to perform mechanistic studies that might elucidate innate immune pathways that are defective in young children. Therefore, new models facilitating control of the timing of infection and cell manipulation are needed to compare the anti-RSV responses of neonatal and adult myeloid cells. An understanding of these mechanisms can aid in the design of new vaccines and therapies. Our long-term research goal is to use a 3D Human Tissue-Engineered Lung Model (3D-HTLM) that exhibits a normal immunological response against infectious agents to elucidate some of the viral and host determinants. The objective of this project is to create a 3D-HTLM that will be used to determine the mechanisms by which immunological immaturity leads to greater RSV pathogenesis. An advantage of the lung model is the ability to test the effect of immunological immaturity by comparing the response of young infants and children vs. adult immune cells to RSV infection. To achieve this goal, the 3D-HTLM will contain the cell types relevant to infection and an inflammatory response, including vascular endothelium, a respiratory epithelium, supporting stromal cells, and myeloid cells, both resident and inflammatory. The 3D-HTLM includes a 3D scaffold and extracellular matrix materials to allow for the correct cell physiological function and cell-to-cell interactions. We will pursue two specific aims. Aim 1: Determine if the lung microenvironment within the 3D-HTLM instructs the differentiation of lung resident myeloid cells. Aim 2: Compare the innate immune response of myeloid cells isolated from neonatal cord blood, young children and adults to RSV infection in the 3D-HTLM. The project will yield new information about the immune response that will provide new targets for preventative and therapeutic interventions of RSV infection, and the tissue-engineered lung model also may be used for testing RSV treatment strategies. In addition, expanding our knowledge about how cells interact with each other and with their environment will vertically advance the field of tissue engineering and the future development of an engineered lung for lung transplantation to treat a variety of lung diseases.

呼吸道合胞病毒（RSV）是全球病毒细支气管炎和肺炎的主要原因，感染第一年的儿童中有70％以上。 RSV会引起婴儿的频繁和严重感染与成人相比。宿主免疫的事实使疫苗的开发变得复杂对RSV的反应在疾病发病机理中起着重要作用。 RSV发病机理的关键可能在于定义与免疫不成熟时的免疫反应不足有关的机制。由于肺居住在婴儿中RSV的反应的研究受到了限制缺乏可用的模型。虽然可以测量气管中存在的细胞因子和趋化因子在RSV支气管炎患者中抽吸，很难获得足够数量的细胞来执行机械可能阐明幼儿有缺陷的先天免疫途径的研究。因此，新的需要促进对感染时间和细胞操纵时间的控制的模型来比较抗RSV 新生儿和成年髓样细胞的反应。对这些机制的理解可以帮助设计新的疫苗和疗法。我们的长期研究目标是使用3D人体组织工程肺模型（3D-HTLM），该模型表现出对传染剂的正常免疫反应，以阐明某些病毒和宿主决定因素。该项目的目的是创建一个3D-HTLM，该3D-HTLM将用于确定其机制免疫学不成熟会导致更大的RSV发病机理。肺模型的优势是能够通过比较儿童与成人的反应来测试免疫学不成熟的影响免疫细胞至RSV感染。为了实现此目标，3D-HTLM将包含与感染和炎症反应，包括血管内皮，呼吸道上皮，支持基质细胞和髓样细胞，均和炎症。 3D-HTLM包括3D脚手架和细胞外基质材料，以允许正确的细胞生理功能和细胞间相互作用。我们将追求两个具体的目标。 AIM 1：确定3D-HTLM中的肺微环境是否指示肺常驻髓样细胞的分化。目标2：比较髓样细胞的先天免疫反应在3D-HTLM中从新生儿脐带血，幼儿和成人分离为RSV感染。该项目将产生有关免疫反应的新信息，该信息将为预防提供新的目标 RSV感染的治疗干预措施以及组织工程肺模型也可用于测试RSV治疗策略。此外，扩展我们有关细胞如何与每个细胞相互作用的知识其他以及他们的环境将垂直促进组织工程领域和未来开发用于肺移植的工程肺部以治疗多种肺部疾病。