Human Biomimetics for Mucosal Infections

整体项目总结 此申请请求是对之前资助的NAMSED合作研究中心的续签 由来自以下机构的基础科学家、内科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)的目标是在实质性进展的基础上再接再厉 其中包括上一次筹资期间发表的42篇使用人类肠道有机化合物(HIO)的出版物和最近发表的 成功制备鼻和肺有机化合物(HNO和HLOS)作为粘膜感染研究的仿生药物 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 了解主要致病因子感染的分子和细胞驱动因素(在本提案中研究) 由于缺乏足够的细胞、动物和人体模型以及大量的宿主依赖， 感染易感性的变异。有机化合物的使用将包括下一代工程，增强 细胞复杂性现在包括免疫和神经细胞与微生物组共培养，整合多个 器官或组织系统，使用许多供体系来检查宿主特有的遗传和对感染的反应， 以及可能改变感染结果的更高阶3D机械生理过程。此BCRC应用程序 整合了一支在病毒学基础研究和翻译研究以及创新方面拥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来检查人类轮状病毒如何 诺如病毒感染的复制和免疫反应受自身免疫和神经细胞的影响 共培养，与其他病原体共感染，以及共生菌。项目2将检查免疫学 呼吸道合胞病毒和冠状病毒在鼻腔和肺器官及自体感染中的反应 免疫细胞建立临床前HNO/HLO模型，重现人类疾病。HIO也会被感染 从力学角度评价呼吸道病毒病的肺肠轴。项目3将确定分子 肠道聚集性大肠埃希菌感染易感性的驱动因素，包括自体免疫协同作用的影响 培养，机械生理线索，如流动和僵硬，以及一个完全完整的肠道系统，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，将是 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-提供有机化合物并建立共培养)，以及工程 微环境科学核心(EMEC)-提供机械生理平台和生物工程 进入有机体系统的线索)。在这一资助期结束时，我们的BCRC团队将推进我们的 对粘膜疾病发生的分子、细胞和机械生理驱动因素的理解 评估有效和安全的治疗方法的新的临床前平台。

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.