Human Biomimetics for Mucosal Infections

用于粘膜感染的人体仿生学

• 批准号: 10462787
• 负责人: Mary Kolb Estes
• 金额: $ 155.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462787
• 关键词: 3-Dimensional; Address; Animal Model; Apical; Autologous; Bacteria; Bacterial Infections; Bacteriology; Bacteriophages; Basic Science; Biocompatible Materials; Biological Models; Biomechanics; Biomedical Engineering; Biomimetics; Cancer Center; Cell model; Cells; Cellular biology; Clinical Microbiology; Coculture Techniques; Communicable Diseases; Communities; Complex; Coronavirus Infections; Cues; Development; Developmental Biology; Disease; Engineering; Enteral; Epithelial; Foundations; Functional disorder; Funding; Gastrointestinal tract structure; Genetic; Genomics; Glycobiology; Goals; Human; Human Biology; Immune; Immune response; Immunology; Infection; Infectious Diseases Research; Institution; Intestinal Mucosa; Intestines; Investigational Drugs; Knowledge; Laboratory Study; Lung; Medical center; Medicine; Methods; Microbe; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Neurons; Norovirus; Nose; Organ; Organoids; Outcome; Oxygen; Pathogenesis; Physicians; Physiological; Physiological Processes; Physiology; Polysaccharides; Population Heterogeneity; Pre-Clinical Model; Predisposition; Productivity; Property; Prophylactic treatment; Proxy; Publications; Request for Applications; Research; Research Personnel; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory syncytial virus; Rice; Role; Rotavirus; SARS-CoV-2 pathogenesis; Scientist; Site; Surface; System; Technology; Testing; Texas; Therapeutic; Tissue Engineering; Tissues; Translating; Translational Research; Universities; Variant; Virus; Virus Diseases; Work; biomaterial development; body system; co-infection; college; commensal bacteria; enteric infection; enteric virus infection; enteroaggregative Escherichia coli; expectation; fluid flow; gastrointestinal infection; genetic manipulation; gut-lung axis; host-microbe interactions; human coronavirus; human disease; human model; innovation; microbial; microbiome; microorganism; mortality; multidisciplinary; next generation; novel; pathogen; pathogenic microbe; physiologic model; pre-clinical; preclinical study; prevent; respiratory; respiratory infection virus; respiratory virus; response; sex; shear stress; stem cell biology; success; synergism; translational approach; virology

OVERALL PROJECT SUMMARY This application request is a renewal of a previous funded NAMSED Cooperative Research Center that encompassed a multidisciplinary team of basic scientists, physician scientists and engineers from institutions in the Texas Medical Center (Baylor College of Medicine, Rice University, and the MD Anderson Cancer Center). The objective of this new Biomimetic Cooperative Research Center (BCRC) is to build upon substantial progress that included 42 publications from the previous funding period to use human intestinal organoids (HIOs) and recent success in making nose and lung organoids (HNOs and HLOs) as biomimetics for the study of mucosal infectious diseases. Enteric and respiratory infections are a leading cause of worldwide morbidity and mortality; our understanding of the molecular and cellular drivers of infection of the key causal agents (studied in this proposal) is hampered due to the lack of sufficient cellular, animal, and human models and substantial host-dependent variation in infection susceptibility. The use of organoids will include next-generation engineering that augments cellular complexity to now include immune and neuronal cell and microbiome co-culture, integration of multiple organ or tissues systems, use of many donor lines to examine host-specific genetics and responses to infection, and higher-order 3D mechano-physiologic processes that may alter infection outcomes. This BCRC application integrates a team with multidisciplinary expertise in basic and translational research and innovation in virology, bacteriology, genomics, developmental biology and physiology, and biomedical engineering and biomaterial development to address important questions in the field. Project 1 will use HIOs to examine how human rotavirus and norovirus infection replication and immune responses are impacted by autologous immune and neuronal cell co-culture, co-infection with other pathogens, and commensal bacteria. Project 2 will examine the immunological response to respiratory syncytial virus and coronavirus infection in nasal and lung organoids and with autologous immune cells to establish preclinical HNO/HLO models that recapitulate human disease. HIOs will also be infected to evaluate mechanistically the lung-gut axis of respiratory virus disease. Project 3 will determine the molecular drivers of susceptibility to infection by enteroaggregative E. coli, including the effect of autologous immune co- culture, mechano-physiologic cues such as flow and stiffness, and a fully integrated intestinal system comprised of all four intestinal segments. All three projects, which have substantial synergy in theme and method, will be supported by three Cores: the Administrative Core (AC - to facilitate governing aspects of the team), Human Biomimetic Scientific Core (HBSC - to provide organoids and establish co-cultures), and the Engineering MicroEnvironment Scientific Core (EMEC - to provide platforms and bioengineering of mechano-physiologic cues into the organoid systems). At the completion of this funded period, our BCRC team will have advanced our understanding of the molecular, cellular and mechano-physiologic drivers of mucosal disease while generating new pre-clinical platforms to evaluate effective and safe therapeutics.

项目总体概要 此申请请求是对先前资助的 NAMSED 合作研究中心的续订，该中心 由来自各机构的基础科学家、医学科学家和工程师组成的多学科团队 德克萨斯医学中心（贝勒医学院、莱斯大学和 MD 安德森癌症中心）。 这个新的仿生合作研究中心 (BCRC) 的目标是在取得实质性进展的基础上再接再厉 其中包括上一个资助期使用人类肠道类器官 (HIO) 和最近的 42 篇出版物 成功制造鼻和肺类器官（HNOs 和 HLOs）作为粘膜感染研究的仿生剂 疾病。肠道和呼吸道感染是全世界发病和死亡的主要原因；我们的 了解关键病原体感染的分子和细胞驱动因素（本提案中研究） 由于缺乏足够的细胞、动物和人类模型以及大量的宿主依赖性而受到阻碍 感染易感性的变化。类器官的使用将包括增强的下一代工程 细胞复杂性现在包括免疫细胞、神经细胞和微生物组共培养、多种细胞的整合 器官或组织系统，使用许多供体系来检查宿主特异性遗传学和对感染的反应， 以及可能改变感染结果的高阶 3D 机械生理过程。此 BCRC 申请 整合了一支在病毒学基础和转化研究及创新方面具有多学科专业知识的团队， 细菌学、基因组学、发育生物学和生理学、生物医学工程和生物材料 发展以解决该领域的重要问题。项目 1 将使用 HIO 来研究人类轮状病毒如何 诺如病毒感染复制和免疫反应受到自体免疫和神经元细胞的影响 共培养、与其他病原体和共生细菌的共感染。项目2将检查免疫学 鼻和肺类器官以及自体器官对呼吸道合胞病毒和冠状病毒感染的反应 免疫细胞建立再现人类疾病的临床前 HNO/HLO 模型。 HIO也会被感染 从机制上评估呼吸道病毒疾病的肺肠轴。项目3将确定分子 肠道聚集性大肠杆菌感染易感性的驱动因素，包括自体免疫共轭作用的影响 培养、机械生理线索（例如流量和硬度）以及完全整合的肠道系统 所有四个肠段。这三个项目在主题和方法上具有实质性的协同性，将 由三个核心支持：行政核心（AC - 促进团队的管理方面）、人力 仿生科学核心（HBSC - 提供类器官并建立共培养物）和工程 微环境科学核心（EMEC - 提供机械生理学平台和生物工程 类器官系统的线索）。在此资助期结束后，我们的 BCRC 团队将推进我们的 了解粘膜疾病的分子、细胞和机械生理驱动因素，同时产生 用于评估有效和安全疗法的新临床前平台。