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Principal Investigator: CALVIN J KUO
Organization: STANFORD UNIVERSITY
Fiscal Year: 2022
Award: $529,054
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY (Core B: Organoid Core)
Infectious disease research is substantially hampered by lack of experimental models necessary to study
interactions between pathogens and target tissues; a glaring deficiency amplified by the recent COVID-19
pandemic. The recent advent of 3D organoid methods embodies a more physiologic in vitro infectious disease
platform. Over the past 5 years, the Stanford NAMSED U19 Center has operated an Organoid Core, led by
Calvin Kuo, which has distributed approximately 74 organoid lines for modeling infectivity of gastrointestinal
pathogens, resulting in numerous collaborative publications. The Organoid Core has also produced new air-
liquid interface (ALI) organoids that maintain epithelium and infiltrating immune populations en bloc without
reconstitution (Cell, 2018) and created new protocols for long-term, feeder-free, chemically defined human lung
distal organoid culture, as well as novel human nasal sinus organoids (Cell Stem Cell, 2020).
The overall goal for Core B (Organoid Core) in our renewal application of the Stanford NAMSED U19 for
a Stanford/UNC Biomimetic U19 Research Center is to expand upon our previous success and provide novel
ex vivo models for studying gastrointestinal and respiratory pathogens. Thus, Core B will serve as a central
biohub for our Center by generating and distributing next-generation human gastrointestinal and respiratory
organoid cultures to support Projects 1-3. In addition to these core responsibilities, the Kuo lab will optimize
innovative organoid-based assays that will provide additional support for Projects 1-3 and resources for the
global research community. In Aim 1, human “epithelial-only” organoids from the stomach, small intestine, distal
lung and nasal airways will be generated, characterized, and distributed for Project 1 (H. pylori, S. Typhi, S.
Typhimurium), Project 2 (rotavirus), and Project 3 (SARS-CoV-2, MERS, pre-epidemic coronaviruses and 1918
influenza H1N1 virus). There has been a particular lack of organoid methods incorporating endogenous immune
populations without reconstitution. Thus, Aim 2 develops innovative ALI organoid methods preserving epithelial
and endogenous infiltrating immune cells en bloc for defining cross-talk between epithelial and immune
compartments during GI and pulmonary infections. Lastly, Aim 3 optimizes multiplexed organoid platforms for
pathogen infection and drug screening to provide novel methods for evaluating infection, therapeutics and
immune responses.
Overall, Core B of the Stanford/UNC Biomimetic U19 Research Center leverages leading-edge expertise
in primary 3D human organoid culture for the study of enteric and respiratory pathogens. Additionally, we
capitalize on novel organoid methods preserving both the epitheilal and immune components to provide
innovative holistic tools to dissect pathways involved during pathogenic infection, with both basic and
translational implications.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><3-D><3-Dimensional><3D><Accessory Sinuses><Air><Alveolar><Alveolus><Assay><Bacterial Model><Bioassay><Biologic Assays><Biological Assay><Biological Mimetics><Biomedical Engineering><Biomimetics><Body Tissues><Bronchial Alveolus><C pylori><C. pylori><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 virus><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><CRISPR><CRISPR activation><CRISPR based activation><CRISPR gene activation><CRISPR interference><CRISPR transcription activation><CRISPR transcriptional activation><CRISPR-Cas-9-mediated gene activation><CRISPR-based gene activation><CRISPR-mediated transcriptional activation><CRISPR/CAS9 activation><CRISPR/CAS9 gene activation><CRISPR/Cas system><CRISPRa><CRISPRi><Campylobacter pylori><Cancer Model><CancerModel><Cancers><Cell Body><Cells><Chemicals><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats interference><CoV-2><CoV2><Communicable Diseases><Communication><Communities><Competence><Coronaviridae><Coronavirus><Development><Distal><Doctor of Philosophy><Drug Screening><Elements><Eperythrozoon><Epidemic><Epithelial><Epithelial Cells><Experimental Models><Feedback><Financial Management><Funding><Generations><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Glare><Goals><Grippe><H pylori><H pylory><H. pylori><H. pylory><H1N1><H1N1 Virus><Haemobartonella><Helicobacter pylori><High Throughput Assay><Histology><Human><Immune><Immune Cell Activation><Immune infiltrates><Immune response><Immunes><Immunologic Model><Immunological Models><Immunological response><In Vitro><Infection><Infectious Agent><Infectious Disease Pathway><Infectious Diseases><Infectious Diseases / Laboratory><Infectious Diseases Research><Infectious Disorder><Influenza><Influenza A Virus, H1N1 Subtype><Information Dissemination><Intestinal><Intestines><Investigators><Liquid substance><Lung><Lung Respiratory System><Lung infections><MERS><MERS coronavirus disease><MERS-CoV disease><Malignant Neoplasms><Malignant Tumor><Methods><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Mission><Modeling><Modern Man><Modification><Murine><Mus><Mycoplasma><Mφ><NIAID><Nasal><Nasal Passages Nose><Nasal Sinuses><Nasal cavity/Paranasal><Nasal cavity/Paranasal sinuses><National Institute of Allergy and Infectious Disease><Nature><Nose><Occupational activity of managing finances><Organoids><Paranasal Sinuses><Pathogenicity><Pathway interactions><Ph.D.><PhD><Physiologic><Physiological><Population><Process><Production><Progenitor Cells><Protocol><Protocols documentation><Publications><Quality Control><Rapid screening><Recombinant DNA Technology><Research><Research Personnel><Research Resources><Researchers><Resources><Respiratory System, Nose, Nasal Passages><Rotavirus><Rotavirus Infections><S enterica serovar Typhi><S enterica serovar Typhimurium><S typhi><S typhimurium><S typhosa><S. enterica Typhimurium><S. enterica serovar Typhi><S. enterica serovar Typhimurium><S. typhi><S. typhimurium><S. typhosa><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Salmonella enterica Typhimurium><Salmonella enterica serovar Typhi><Salmonella enterica serovar Typhimurium><Salmonella typhi><Salmonella typhimurium><Salmonella typhosa><Scientific Publication><Services><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Sinus><Small Intestines><Specialty><Standardization><Stomach><Study models><System><T cell infiltration><T cell tumor trafficking><Techniques><Terminal Bronchiole><Testing><Therapeutic><Tissues><Tumor-infiltrating immune cells><Wuhan coronavirus><bacteria pathogen><bacterial pathogen><base><bio-engineered><bio-engineers><bioengineering><biological engineering><bowel><cell type><corona virus><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><developmental><dissemination of results><empowered><enteral pathogen><enteric pathogen><enteropathogen><entire genome><experience><fluid><full genome><gastric><gastric organoids><gastroid><gastrointestinal><genetically engineered><genome sequencing><global health><hCoV19><high throughput screening><host response><immune activation><immune cell infiltrate><immune infiltration><immune system response><immunoresponse><improved><in vitro Model><infectious organism><innovate><innovation><innovative><intestinal pathogen><intestine pathogen><intratumoral immune cell><liquid><macrophage><malignancy><medical specialties><nCoV2><neoplasm/cancer><network models><new drug treatments><new drugs><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathogen><pathogenic bacteria><pathway><preservation><programs><pulmonary><pulmonary infections><reconstitute><reconstitution><respiratory><respiratory pathogen><response><response to therapy><response to treatment><scRNA-seq><screening><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small bowel><socio-economic><socio-economically><socioeconomically><socioeconomics><stem cells><stomach organoid><success><synergism><therapeutic response><therapy response><three dimensional><tool><treatment response><tumor immune cell><whole genome>