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Human Biomimetics for Mucosal Infections

用于粘膜感染的人体仿生学

基本信息

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
项目类别：
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

项目摘要

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.

项目总体总结