Human Biomimetics for Mucosal Infections

总体项目摘要 该申请是对先前资助的NAMSED合作研究中心的更新， 包括来自世界各地的基础科学家、医生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）。 这个新的仿生学合作研究中心（BCRC）的目标是在取得实质性进展的基础上， 其中包括上一个资助期的42篇使用人类肠道类器官（HIOs）的出版物，以及最近的 成功制造鼻和肺类器官（HNO和HLO）作为粘膜感染研究的仿生学 疾病肠道和呼吸道感染是全球发病率和死亡率的主要原因;我们的 了解感染关键致病因子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， 感染易感性的变化。类器官的使用将包括下一代工程， 细胞复杂性现在包括免疫和神经元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。巴塞尔公约区域中心的这一申请 整合了一个在病毒学基础和转化研究以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HIOs来研究人类轮状病毒如何 诺如病毒感染复制和免疫应答受自体免疫和神经细胞的影响 共培养、与其他病原体和肠道细菌共感染。项目2将检查免疫学 对鼻和肺类器官中呼吸道合胞病毒和冠状病毒感染的反应以及自体 免疫细胞来建立重现人类疾病的临床前HNO/HLO模型。HIO也会被感染 从机制上评价呼吸道病毒病的肺-肠轴。项目3将确定分子 肠聚集性E.大肠杆菌，包括自体免疫的影响， 文化，机械生理学线索，如流动和刚度，以及完全整合的肠道系统，包括 所有四个肠段。这三个项目在主题和方法上都有很大的协同作用， 由三个核心支持：行政核心（AC -促进团队的管理方面）， 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）-提供机械生理学的平台和生物工程 进入类器官系统的线索）。在这一供资期结束时，我们的《巴塞尔公约》区域中心团队将推进我们的 了解粘膜疾病的分子，细胞和机械生理驱动因素， 新的临床前平台，以评估有效和安全的治疗方法。

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.