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.

总体项目摘要 该申请请求是对以前的著名合作研究中心的续签 包括一个由基础科学家，医师科学家和工程师组成的多学科团队 德克萨斯医学中心（莱斯大学贝勒医学院和医学博士安德森癌症中心）。 这个新的仿生合作研究中心（BCRC）的目的是基于实质性进步 其中包括上一张资金期的42个出版物，用于使用人类肠癌（HIO）和最近 成功制作鼻子和肺类器官（HNOS和HLOS）作为粘膜传染性研究 疾病。肠和呼吸道感染是全球发病率和死亡率的主要原因。我们的 了解关键因果剂感染的分子和细胞驱动因素（在此提案中进行了研究） 由于缺乏足够的细胞，动物和人类模型以及实质性宿主依赖性而受到阻碍 感染敏感性的变化。器官的使用将包括增强的下一代工程 现在的细胞复杂性包括免疫和神经元细胞以及微生物组共培养，多个的整合 器官或组织系统，使用许多供体线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应用程序 将团队与病毒学基础和翻译研究与创新方面的多学科专业知识相结合， 细菌学，基因组学，发育生物学和生理学以及生物医学工程和生物材料 开发以解决该领域的重要问题。项目1将使用HIO检查人轮状病毒的方式 自体免疫和神经元细胞影响诺如病毒感染的复制和免疫反应 共培养，与其他病原体共同感染和共生细菌。项目2将检查免疫学 对鼻和肺器官中呼吸道合胞病毒和冠状病毒感染的反应 免疫细胞建立临床前HNO/HLO模型，以概括人类疾病。 HIO也将被感染 从机械上评估呼吸病毒疾病的肺轴。项目3将确定分子 通过肠球形大肠杆菌感染感染的驱动力，包括自体免疫共同的影响 培养，机械生理线索，例如流量和刚度，以及完全集成的肠系统 在所有四个肠段中。这三个项目在主题和方法上具有实质性协同作用，将是 在三个核心的支持下：行政核心（AC-促进团队的管理方面），人类 仿生科学核心（HBSC-提供器官并建立共同培养）和工程学 微环境科学核心（EMEC-提供机械生理学的平台和生物工程 提示进入器官系统）。在这一资助时期的完成时，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 新的临床前平台评估有效且安全的治疗疗法。