Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1384&sort=award_id
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=award_id", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1424&sort=award_id", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1385&sort=award_id", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1383&sort=award_id" }, "data": [ { "type": "Grant", "id": "11000", "attributes": { "award_id": "5U19AG073172-02", "title": "Phenotyping and Biospecimen Core", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Aging (NIA)" ], "program_reference_codes": [], "program_officials": [], "start_date": "2021-09-30", "end_date": "2026-08-31", "award_amount": 1440598, "principal_investigator": { "id": 24449, "first_name": "Stacy", "last_name": "Andersen", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 860, "ror": "", "name": "BOSTON UNIVERSITY MEDICAL CAMPUS", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 860, "ror": "", "name": "BOSTON UNIVERSITY MEDICAL CAMPUS", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "The Phenotyping and Biospecimen (P&B) Core's primary mission is to leverage two NIA-funded centenarian studies by sifting through their study participants in identifying centenarian cognitive superagers, offspring and offspring spouses for enrollment in the RADCO study, extending their phenotyping with annual uniform neuropsychological testing, plasma biomarkers of Alzheimer's disease (AD), and facilitating and facilitating neuroimaging and post-mortem neuropathological studies among willing participants. The P&B Core's successful conduct of its six aims is critical to RADCO's investigation of centenarians and their offspring as models of cognitive resilience and resistance to cognitive impairment and AD. Those 6 Specific Aims are: Specific Aim 1. Establish a cognitive superagers (n=496, ages 100-110 years), offspring (n=600), and offspring spouses (n=120) sample with baseline neuropsychological assessments, other phenotypic data, blood samples, and genetic and biomarker data provided by 2 ongoing NIA-funded centenarian studies. Specific Aim 2. Perform annual Covid-19-safe virtual neurocognitive assessments and other phenotypic data collection that are uniform with the ILO study and LCCP measures. Also, to enhance accuracy of the neurocognitive assessments by performing interdisciplinary expert diagnoses consensus conferences. Specific Aim 3. Employing REDCap, manage and perform QC, and make easily but securely available all of the data collected and generated by the RADCO Cores and Projects, including the neuropsychological, neuroimaging, neuropathologic phenotype and biomarker and transcriptomic data. Specific Aim 4. To receive from the ILO+LCCP studies and then longitudinally collect blood samples (centenarians annually, offspring and offspring spouses every other year) from RADCO participants for use by the two projects. To maintain samples in a biorepository as a sharable resource. Specific Aim 5. Support the RADCO Neuroimaging Core's aims by recruiting RADCO participants for local neuroimaging and linking scan data to clinical data. Specific Aim 6. Recruit RADCO participants for future brain donation, ensure that autopsies proceed smoothly, and link clinical data to anatomic, pathologic and molecular data generated by the P&B neuropathology efforts. These data will inform the resilient and resistant phenotypes delineated in Project 1. Brain area-specific tissues will be provided for RNA expression studies in Project 2.", "keywords": [ "Affect", "Age", "Alzheimer&apos", "s Disease", "Alzheimer’s disease biomarker", "Amyloid beta-42", "Anatomy", "Area", "Autopsy", "Biological", "Biological Assay", "Blood specimen", "Boston", "Brain", "COVID-19", "Centenarian", "Clinical Data", "Cognitive", "Consensus", "Data", "Data Collection", "Dementia", "Diagnosis", "Disease Marker", "Elderly", "Eligibility Determination", "Enrollment", "Ensure", "Familiarity", "Fasting", "Funding", "Future", "Gene Expression", "Genetic Markers", "Genetic Transcription", "Impaired cognition", "Impairment", "Investigation", "Knowledge Portal", "Lead", "Link", "Longevity", "Los Angeles", "Measures", "Mission", "Modeling", "Molecular", "Neurocognitive", "Neuropsychological Tests", "Neuropsychology", "New York City", "Outcome", "Participant", "Pathologic", "Patient Recruitments", "Phenotype", "Plasma", "RNA", "Research Personnel", "Resistance", "Resource Sharing", "Resources", "Sampling", "Scanning", "Secure", "Spouses", "Statistical Data Interpretation", "System", "Time", "Tissues", "Work", "base", "biobank", "cognitive function", "cytokine", "data de-identification", "data management", "data sharing", "exome", "experience", "innovation", "neuroimaging", "neuropathology", "offspring", "phenotypic biomarker", "phenotypic data", "protective factors", "recruit", "resilience", "success", "symposium", "tool", "transcriptomics", "virtual" ], "approved": true } }, { "type": "Grant", "id": "6673", "attributes": { "award_id": "5U19AI057266-19", "title": "Project 1: Immune Memory", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [], "start_date": "2003-09-01", "end_date": "2024-04-30", "award_amount": 726394, "principal_investigator": { "id": 22348, "first_name": "Rafi", "last_name": "Ahmed", "orcid": null, "emails": "[email protected]", "private_emails": null, "keywords": "[]", "approved": true, "websites": "[]", "desired_collaboration": "", "comments": "", "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 265, "ror": "https://ror.org/03czfpz43", "name": "Emory University", "address": "", "city": "", "state": "GA", "zip": "", "country": "United States", "approved": true }, "abstract": "The over-arching goal of this proposal is to analyze SARS-CoV-2 antibody seroconversion rates in health care workers at the Emory University Hospital over the next year and to study adaptive immune responses to SARS-CoV-2 infection during acute infection and at convalescence. These studies will draw on three main sources of samples, either through an emerging infectious disease protocol at the Emory Vaccine Center Hope Clinic, through a sero-surveillance study initiated at Emory, and previously collected PBMC and serum samples from adult or elderly donors by Dr. Jorg Goronzy, respectively. We will develop and employ a combination of antibody binding assays and viral neutralization assays to test the quantity and quality of the infection-induced antibody responses. This information will also be used to identify optimal donors for single-cell antibody expression cloning, as we have previously described9-13. A recently purchased 10x instrument in our BSL3 facility at the Emory Vaccine Center will allow for a detailed analysis of the transcriptional profiles of innate and adaptive immune responses during acute SARS-CoV-2 infection. The proposed studies will provide key insight into the dynamics of this devastating disease among health care workers at a major metropolitan hospital in Atlanta. These efforts will also generate key serological tools, provide an understanding of the humoral immune response to SARS-CoV-2 infection, and generate human monoclonal antibodies, with both diagnostic and therapeutic potential.", "keywords": [ "2019-nCoV", "Acute", "Adult", "Antibodies", "Antibody Response", "B-Lymphocytes", "Binding", "Biological Assay", "Cells", "Clinic", "Convalescence", "Coronavirus", "Development", "Diagnostic", "Disease", "Elderly", "Emerging Communicable Diseases", "Gene Expression Profile", "Goals", "Health Personnel", "Human", "Humoral Immunities", "Immune response", "Immunologic Memory", "Infection", "Peripheral Blood Mononuclear Cell", "Protocols documentation", "SARS-CoV-2 antibody", "SARS-CoV-2 infection", "Sampling", "Serology", "Serology test", "Serum", "Source", "Testing", "Therapeutic", "University Hospitals", "Urban Hospitals", "Vaccines", "Viral", "Virus", "Virus Diseases", "acute infection", "adaptive immune response", "aged", "biosafety level 3 facility", "expression cloning", "human monoclonal antibodies", "insight", "instrument", "response", "seroconversion", "serosurveillance", "tool", "vaccine-induced immunity" ], "approved": true } }, { "type": "Grant", "id": "7676", "attributes": { "award_id": "5U19AI100625-09", "title": "Systems Immunogenetics of Biodefense and Emerging Pathogens in the Collaborative Cross", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 6173, "first_name": "QIAN", "last_name": "Liu", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2012-08-05", "end_date": "2022-08-31", "award_amount": 2332322, "principal_investigator": { "id": 6339, "first_name": "Ralph S", "last_name": "Baric", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 456, "ror": "https://ror.org/05dq2gs74", "name": "Vanderbilt University Medical Center", "address": "", "city": "", "state": "TN", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [ { "id": 8308, "first_name": "Mark T", "last_name": "Heise", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 817, "ror": "", "name": "UNIV OF NORTH CAROLINA CHAPEL HILL", "address": "", "city": "", "state": "NC", "zip": "", "country": "United States", "approved": true }, "abstract": "Abstract: Emerging viruses, such as SARS-CoV, influenza A virus (IAV), and West Nile virus (WNV) cause high levels of morbidity and mortality in human populations. Host immune responses can play either protective or a pathologic role during viral infections. Therefore, understanding of the regulatory networks and signaling pathways that determine the magnitude and quality of an individual's antiviral immune response has important implications for human health, since these genes/pathways could be therapeutically targeted to treat virus- induced disease, or may represent targets for enhancing the safety and efficacy of vaccines against a wide range of viral pathogens. Polymorphic host genes and regulatory networks have a major impact on immune response variation in human populations. However, confounding environmental factors and/or ethical concerns limit the types of studies that can be conducted in humans. Therefore, genetically tractable model systems that capture the range of genetic and phenotypic diversity seen in humans, such as the Collaborative Cross (CC) are needed to mechanistically dissect the genetics of immune variation. Our research team has quantified variation in baseline, as well as SARS-CoV, IAV, and WNV-induced immune responses in a panel of 110 CC RIX lines (reproducible F1 crosses between CC recombinant inbred (RI) lines that model heterozygous human populations). To our knowledge, this represents to most comprehensive analysis of immune response variation ever conducted in a genetic reference population, and in ongoing QTL mapping studies, we have identified 100+ quantitative trait loci (QTL) associated with variation in virus-induced innate and adaptive immunity, inflammation and disease. Our program, which includes expertise in viral pathogenesis, innate and adaptive immunity, and quantitative genetics will use this unprecedented data base to: 1) identify and characterize polymorphic host genes that drive variation in virus-induced disease, 2) test how interactions between different polymorphic genes/loci shape the host immune response, 3) test how these genes impact responses to other viral pathogens, or function during allergy/auto-immunity, and 4) test the impact of these genes in the context of human infections to identify targets for diagnosis, prevention and therapeutic interventions in humans. These studies will significantly enhance our understanding of how host genetic variation shapes virus-induced immunity and/or disease.", "keywords": [ "Affect", "Antiviral Agents", "Autoimmunity", "Automobile Driving", "Biological Models", "Clustered Regularly Interspaced Short Palindromic Repeats", "Data Set", "Databases", "Diagnosis", "Disease", "Environmental Risk Factor", "Ethics", "Gene Combinations", "Genes", "Genetic", "Genetic Variation", "Health", "Human", "Hypersensitivity", "Immune", "Immune System Diseases", "Immune response", "Immunity", "Immunogenetics", "Inbreeding", "Individual", "Infection", "Inflammation", "Influenza A virus", "Maps", "Mediating", "Modeling", "Morbidity - disease rate", "Mus", "Natural Immunity", "Pathogenesis", "Pathologic", "Pathway interactions", "Phenotype", "Play", "Population", "Preventive Intervention", "Quantitative Genetics", "Quantitative Trait Loci", "Recombinants", "Reproducibility", "Research", "Research Design", "Role", "SARS coronavirus", "Sampling", "Shapes", "Signal Pathway", "System", "Testing", "Therapeutic Intervention", "Time", "Variant", "Viral Pathogenesis", "Virus", "Virus Diseases", "West Nile virus", "adaptive immunity", "biodefense", "cohort", "genome editing", "genomic locus", "mortality", "mouse genetics", "pathogen", "pathogenic virus", "programs", "respiratory virus", "response", "therapeutic target", "tool", "vaccine efficacy", "vaccine safety" ], "approved": true } }, { "type": "Grant", "id": "6613", "attributes": { "award_id": "5U19AI116484-07", "title": "Stanford/UNC Biomimetic U19 Research Center", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 22202, "first_name": "Rodolfo M.", "last_name": "Alarcon", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2015-03-01", "end_date": "2026-03-31", "award_amount": 1511551, "principal_investigator": { "id": 22203, "first_name": "MANUEL R", "last_name": "AMIEVA", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 22204, "first_name": "CALVIN J", "last_name": "KUO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 266, "ror": "https://ror.org/00f54p054", "name": "Stanford University", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Stanford/UNC Biomimetic U19 Research Center PROJECT SUMMARY/ABSTRACT – CENTER OVERVIEW Infectious diseases continue to pervasively afflict global health and socioeconomic stability despite substantial prevention and treatment initiatives. Respiratory and gastrointestinal pathogens rank amongst the most intractable infectious diseases, particularly notable for recurrent waves of zoonotic coronaviruses and the recent COVID-19 pandemic, engendered by SARS-CoV-2. Overall, an urgent need exists for improved in vitro experimental models of human disease to study pathogenesis and to validate therapeutics. The central mission of the Stanford/UNC Biomimetic U19 Research Center is thus to deploy novel 3-dimensional organoid culture models to elucidate the biology and therapy of respiratory and gastrointestinal infectious pathogens. Our application is a renewal of our prior Stanford NAMSED U19 Research Center and is comprised of two Cores and three research Projects, leveraging complementary and synergistic expertise of our investigators at Stanford University and the University of North Carolina. The Center continues to be led by the Multi-PIs, Calvin Kuo and Manuel Amieva, who also co-lead Core A (Administrative Core). Core B (Organoid Core) is led by Calvin Kuo and provides novel capabilities for lung and GI organoid culture, gene editing and multiplexed screening. The three Projects extensively utilize organoid biomimetics for exploration of GI and respiratory pathogens. Project 1, (PI, Manuel Amieva) investigates H. pylori and Salmonella colonization, competition and invasion in the GI tract, while Project 2 (PI, Harry Greenberg) investigates rotavirus host range, neutralization, and M cell interactions in enteric biomimetics. Project 3 (PI, Ralph Baric) is a new addition and extensively uses organoids to model SARS-CoV-2, other closely related epidemic and pre-epidemic emerging coronaviruses and 1918 H1N1 influenza to reveal common and unique host networks associated with severe pulmonary outcomes. The activities of the Stanford/UNC Biomimetic U19 Research Center reside within three overarching Aims. In Aim 1, our Center performs organoid modeling of the epithelium-pathogen interface to investigate pathogenesis, susceptibility and host range restriction. This employs robust reverse genetics and CRISPR screens to systematically manipulate host versus viral/bacterial compartments, within novel apical-basal polarity modulated distal lung/alveolar, nasal sinus, stomach and intestinal organoid systems. Aim 2 defines how SARS- CoV-2, pre-epidemic coronaviruses, rotavirus and Salmonella can perturb reciprocal cross-talk between tissue epithelium and resident immune cells. This exploits a unique 3D air-liquid interface organoid method preserving GI and lung epithelium en bloc with diverse endogenous infiltrating immune cell types without artificial reconstitution. Lastly, Aim 3 performs organoid-based evaluation of therapeutic candidates against SARS-CoV- 2, pre-epidemic coronaviruses and rotavirus in medium- to high-throughput formats including epithelium and/or immune cells. Overall, the explorations of the Stanford/UNC Biomimetic U19 Research Center directly apply advanced organoid systems to the investigation and therapy of recalcitrant infectious pathogens.", "keywords": [ "2019-nCoV", "3-Dimensional", "Acute", "Acute Respiratory Distress Syndrome", "Air", "Alveolar", "Apical", "Bacteria", "Bacterial Infections", "Basic Science", "Binding", "Biology", "Biomimetics", "COVID-19", "COVID-19 pandemic", "COVID-19 test", "CRISPR interference", "CRISPR screen", "CRISPR-mediated transcriptional activation", "Cell Communication", "Cells", "Chiroptera", "Chronic", "Clustered Regularly Interspaced Short Palindromic Repeats", "Coculture Techniques", "Communicable Diseases", "Coronavirus", "Digestion", "Disease", "Distal", "Enteral", "Epidemic", "Epithelial", "Epitopes", "Escherichia coli", "Etiology", "Exhibits", "Experimental Models", "Functional disorder", "Gastrointestinal Diseases", "Gastrointestinal tract structure", "Genes", "Genetic Screening", "Glycoproteins", "Goals", "Growth", "Helicobacter pylori", "Human", "Immune", "Immune response", "Immunity", "In Vitro", "Incubators", "Infection", "Influenza", "Influenza A Virus H1N1 Subtype", "Intestines", "Investigation", "Investigational Therapies", "Lead", "Liquid substance", "Lung", "Lung infections", "M cell", "Mediating", "Methods", "Middle East", "Middle East Respiratory Syndrome", "Middle East Respiratory Syndrome Coronavirus", "Mission", "Modeling", "Monoclonal Antibodies", "Morbidity - disease rate", "Myelogenous", "National Institute of Allergy and Infectious Disease", "Norovirus", "North Carolina", "Organoids", "Outcome", "Pathogenesis", "Pathogenicity", "Play", "Pneumonia", "Population", "Predisposition", "Prevention", "Pulmonary alveolar structure", "Recurrence", "Research", "Research Personnel", "Research Project Grants", "Resistance", "Respiratory Failure", "Respiratory Mucosa", "Respiratory Therapy", "Respiratory Tract Infections", "Role", "Rotavirus", "Route", "SARS coronavirus", "SARS-CoV-2 inhibitor", "Salmonella", "Salmonella typhi", "Salmonella typhimurium", "Severe Acute Respiratory Syndrome", "Sinus", "Stomach", "Surface", "System", "Terminal Bronchiole", "Testing", "Therapeutic", "Time", "Tissue Engineering", "Tissues", "Tumor-infiltrating immune cells", "Universities", "Viral", "Virulence", "Virus", "Virus Diseases", "Zoonoses", "absorption", "adaptive immune response", "airway epithelium", "base", "cell type", "comparative", "cytokine release syndrome", "emerging pathogen", "enteric infection", "gastric organoids", "gastrointestinal", "gastrointestinal epithel" ], "approved": true } }, { "type": "Grant", "id": "6826", "attributes": { "award_id": "5U19AI116497-07", "title": "Human Biomimetics for Mucosal Infections", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 6817, "first_name": "Rodolfo M.", "last_name": "Alarcon", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2015-03-15", "end_date": "2026-05-31", "award_amount": 1557840, "principal_investigator": { "id": 22650, "first_name": "Mary Kolb", "last_name": "Estes", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 566, "ror": "https://ror.org/02pttbw34", "name": "Baylor College of Medicine", "address": "", "city": "", "state": "TX", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [ { "id": 22651, "first_name": "ANTHONY W", "last_name": "MARESSO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, { "id": 22652, "first_name": "Pedro A", "last_name": "Piedra", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 566, "ror": "https://ror.org/02pttbw34", "name": "Baylor College of Medicine", "address": "", "city": "", "state": "TX", "zip": "", "country": "United States", "approved": true }, "abstract": "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.", "keywords": [ "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 infec" ], "approved": true } }, { "type": "Grant", "id": "5946", "attributes": { "award_id": "5U19AI131130-05", "title": "Engineering a human brain organoid-based platform to study neurotropic viruses", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 20288, "first_name": "KAITLYN MELISSA", "last_name": "Morabito", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2017-04-01", "end_date": "2023-03-31", "award_amount": 1499160, "principal_investigator": { "id": 20289, "first_name": "Guo-li", "last_name": "Ming", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 20290, "first_name": "HENGLI", "last_name": "TANG", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 232, "ror": "https://ror.org/00b30xv10", "name": "University of Pennsylvania", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "– Overview Modeling of infectious diseases that affect the human central nervous system (CNS), such as those associated with Zika virus (ZIKV) and West Nile virus (WNV), has been challenging due to the inaccessibility of the relevant cell types. Reprogramming human somatic cells, such as skin fibroblasts, into induced pluripotent stem cells (iPSCs) provides a genetically tractable and renewable source of human neural cell populations. We can differentiate these iPSCs into many of the cell types critical for the study of neurotropic viruses, but typically this is performed in monolayer cultures to allow for more control and to generate more homogeneous cell populations, but this methodology lacks the self-organizing properties and interactive dynamics among different cell populations observed during organ development. Recently, more complex structures resembling whole developing organs, named organoids, have been generated from human iPSCs via 3D culturing methods. This emerging new technology has the potential to significantly advance our understanding of infectious diseases and for future therapeutic development. The success of this approach, however, critically depends on how well organoids mimic biological structures, recapitulate human physiology and disease pathology, and incorporate components critical to disease and human host responses. We propose to develop a robust platform for organoid development to model brain development that can be adopted by single labs for basic research, and is amenable to translational studies and drug development and testing. Our Research Center is comprised of three Research Projects, a Scientific Core, and an Administrative Core led by experts in virology, stem cell biology, neural development, and bioengineering. We will focus on ZIKV and WNV, two neurotropic flaviviruses, to develop our organoid platform, which can then be used by the scientific community to investigate other infectious diseases that affect the nervous system. Importantly, ZIKV and WNV are thought to impact the CNS at different stages of development, with ZIKV having been recently implicated as being causal for microcephaly in some pregnant women. This affords us the opportunity to develop an organoid platform with proof-of-principle testing with viruses suspected to have cell type- and stage-specific tropism. Project 1 will focus on technology development to generate more mature organoids and the scaling up of robust assays to perform medium-throughput compound testing. Project 2 will focus on ZIKV infections in early stage organoids and Project 3 will evaluate co-culture organoid systems to model WNV infections in later stage organoids. The projects will be supported by a Scientific Core that will provide cells and on-site training to Projects 2 & 3, as well as optimization of differentiation protocols and bioinformatics analyses. Finally, the Administrative Core will provide logistical support to facilitate collaborations among investigators and to coordinate the timely release of results and resources to the scientific community.", "keywords": [ "3-Dimensional", "Ache", "Address", "Adherent Culture", "Adopted", "Adult", "Affect", "Americas", "Animals", "Arthralgia", "Basic Science", "Bioinformatics", "Biological", "Biological Assay", "Biology", "Biomedical Engineering", "Brain", "Cell model", "Cell physiology", "Cells", "Centers for Disease Control and Prevention (U.S.)", "Central Nervous System Infections", "Central Nervous System Viral Diseases", "Cerebrum", "Coculture Techniques", "Collaborations", "Communicable Diseases", "Communities", "Complex", "Custom", "Data", "Decision Making", "Development", "Diarrhea", "Disease", "Disease Outbreaks", "Encephalitis", "Engineering", "Epidemic", "Exanthema", "Fibroblasts", "Flavivirus", "Flavivirus Infections", "Fostering", "Future", "Generations", "Goals", "Headache", "Human", "Immune response", "Infectious Diseases Research", "Institutes", "Intervention", "Laboratories", "Lead", "Logistics", "Meningitis", "Methodology", "Methods", "Microcephaly", "Mitotic", "Modeling", "Molecular", "Names", "Nervous system structure", "Neuraxis", "Neurologic", "Neurological outcome", "Neurons", "Organ", "Organoids", "Pathology", "Pharmaceutical Preparations", "Physiology", "Population", "Pregnant Women", "Proliferating", "Property", "Protocols documentation", "Rapid diagnostics", "Research", "Research Personnel", "Research Project Grants", "Resources", "Site", "Skin", "Somatic Cell", "Source", "Standardization", "Structure", "System", "Technology", "Testing", "Therapeutic Intervention", "Time", "Training", "Translational Research", "Tropism", "Validation", "Viral", "Viral Pathogenesis", "Virus", "Vomiting", "West Nile viral infection", "West Nile virus", "ZIKV infection", "Zika Virus", "base", "cell type", "cost", "data resource", "data sharing", "design", "differentiation protocol", "drug development", "drug testing", "fetal", "flexibility", "functional outcomes", "global health", "human stem cells", "human tissue", "in vitro Model", "induced pluripotent stem cell", "infectious disease model", "member", "molecular pathology", "nerve stem cell", "neurodevelopment", "neurotropic", "neurotropic virus", "new technology", "organ growth", "programs", "response", "scale up", "screening", "stem cell biology", "stem cell differentiation", "stem cell model", "success", "technology development", "therapeutic development", "therapeutic evaluation", "therapeutically effective", "three dimensional cell culture", "translat" ], "approved": true } }, { "type": "Grant", "id": "7654", "attributes": { "award_id": "5U19AI135995-03", "title": "Consortium for Viral Systems Biology (CViSB)", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 6044, "first_name": "REED SOLOMON", "last_name": "Shabman", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2018-02-01", "end_date": "2023-01-31", "award_amount": 2550000, "principal_investigator": { "id": 6045, "first_name": "Kristian Graugaard", "last_name": "Andersen", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 745, "ror": "", "name": "SCRIPPS RESEARCH INSTITUTE, THE", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 745, "ror": "", "name": "SCRIPPS RESEARCH INSTITUTE, THE", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Modified Project Summary/Abstract Section The Ebola epidemic that ravaged West Africa from 2013 to 2016 is by far the largest outbreak ever recorded. Weak healthcare infrastructure, community resistance, and a slow uncoordinated response allowed the epidemic to spin out of control. The region, however, is no stranger to dealing with viral hemorrhagic fevers. Lassa fever is caused by infection with Lassa virus and is hyper-endemic in West Africa. Lassa fever is similar to Ebola in that infection with Lassa virus can lead to a severe hemorrhagic fever. Infections with both Lassa virus and Ebola virus can lead to deaths in more than 70% of hospitalized patients. It is estimated that tens of thousands of people die from Lassa fever each year. These numbers are likely underestimates, as the healthcare infrastructure in the affected countries is extremely weak, surveillance almost non-existent, and most patients never present in the hospital. Despite the high case fatality rates of hospitalized Ebola and Lassa fever patients, however, some people appear to be able to quickly fight the viruses, whereas others die quickly from infection. Yet, what distinguishes fatal from non-fatal disease and the development of symptomatic versus asymptomatic infection, remain largely unknown and severely understudied. The recent COVID-19 global pandemic has presented identical challenges and research questions as Ebola and Lassa Fever. The goal of the Consortium for Viral Systems Biology is to uncover the virus and human factors that determine how infected individuals are able to better fight the viruses. We will achieve this goal by investigating the following three broad aims: Aim 1. Define virus and host factors responsible for survival and non-survival in Ebola, Lassa fever and COVID-19 patients. Aim 2. Identify factors that play roles in the development of severe long-term symptoms in survivors. Aim 3. Define factors that determine whether human individuals develop symptomatic or asymptomatic disease. We will accomplish these aims by applying several ‘omics’ technologies, physiological measurements, and high-throughput experimental approaches to unique patient and survivor cohorts of COVID-19, Lassa fever and Ebola. We will develop novel predictive statistical models for identifying critical disease correlates and analyze large-scale data sets to pinpoint causal host-pathogen interactions. By elucidation the molecular networks that play critical roles in patient outcomes, this research will allow us to identify new targets for medicines and vaccines and inform personalized treatment strategies. Our study will also provide novel research frameworks and computational algorithms applicable to a wide range of other human pathogens.", "keywords": [ "Address", "Affect", "Africa", "Binding", "Biological", "Case Fatality Rates", "Cessation of life", "Clinical", "Communities", "Computational algorithm", "Country", "Data Set", "Development", "Disease", "Disease Marker", "Disease Outbreaks", "Ebola", "Ebola Hemorrhagic Fever", "Ebola virus", "Epidemic", "Future", "Genetic", "Goals", "Healthcare", "Hospitals", "Human", "Immunologics", "Immunotherapeutic agent", "Individual", "Infection", "Infrastructure", "Integration Host Factors", "Investigation", "Lassa Fever", "Lassa virus", "Lead", "Measurement", "Medicine", "Mission", "Molecular", "Outcome", "Outcomes Research", "Patient-Focused Outcomes", "Patients", "Physiological", "Play", "Research", "Research Infrastructure", "Resistance", "Role", "Severities", "Statistical Models", "Survivors", "Symptoms", "System", "Systems Biology", "Technology", "Vaccines", "Viral", "Viral Hemorrhagic Fevers", "Virus", "Work", "cohort", "data access", "data tools", "fighting", "human disease", "human pathogen", "innovation", "insight", "large scale data", "member", "microbial", "neutralizing antibody", "novel", "pathogen", "personalized medicine", "predictive marker", "predictive modeling", "programs", "response", "treatment strategy" ], "approved": true } }, { "type": "Grant", "id": "6639", "attributes": { "award_id": "5U19AI135995-05", "title": "Consortium for Viral Systems Biology (CViSB)", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 22268, "first_name": "REED SOLOMON", "last_name": "Shabman", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2018-02-01", "end_date": "2023-01-31", "award_amount": 2550000, "principal_investigator": { "id": 22269, "first_name": "Kristian Graugaard", "last_name": "Andersen", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 745, "ror": "", "name": "SCRIPPS RESEARCH INSTITUTE, THE", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Modified Project Summary/Abstract Section The Ebola epidemic that ravaged West Africa from 2013 to 2016 is by far the largest outbreak ever recorded. Weak healthcare infrastructure, community resistance, and a slow uncoordinated response allowed the epidemic to spin out of control. The region, however, is no stranger to dealing with viral hemorrhagic fevers. Lassa fever is caused by infection with Lassa virus and is hyper-endemic in West Africa. Lassa fever is similar to Ebola in that infection with Lassa virus can lead to a severe hemorrhagic fever. Infections with both Lassa virus and Ebola virus can lead to deaths in more than 70% of hospitalized patients. It is estimated that tens of thousands of people die from Lassa fever each year. These numbers are likely underestimates, as the healthcare infrastructure in the affected countries is extremely weak, surveillance almost non-existent, and most patients never present in the hospital. Despite the high case fatality rates of hospitalized Ebola and Lassa fever patients, however, some people appear to be able to quickly fight the viruses, whereas others die quickly from infection. Yet, what distinguishes fatal from non-fatal disease and the development of symptomatic versus asymptomatic infection, remain largely unknown and severely understudied. The recent COVID-19 global pandemic has presented identical challenges and research questions as Ebola and Lassa Fever. The goal of the Consortium for Viral Systems Biology is to uncover the virus and human factors that determine how infected individuals are able to better fight the viruses. We will achieve this goal by investigating the following three broad aims: Aim 1. Define virus and host factors responsible for survival and non-survival in Ebola, Lassa fever and COVID-19 patients. Aim 2. Identify factors that play roles in the development of severe long-term symptoms in survivors. Aim 3. Define factors that determine whether human individuals develop symptomatic or asymptomatic disease. We will accomplish these aims by applying several ‘omics’ technologies, physiological measurements, and high-throughput experimental approaches to unique patient and survivor cohorts of COVID-19, Lassa fever and Ebola. We will develop novel predictive statistical models for identifying critical disease correlates and analyze large-scale data sets to pinpoint causal host-pathogen interactions. By elucidation the molecular networks that play critical roles in patient outcomes, this research will allow us to identify new targets for medicines and vaccines and inform personalized treatment strategies. Our study will also provide novel research frameworks and computational algorithms applicable to a wide range of other human pathogens.", "keywords": [ "2019-nCoV", "Address", "Affect", "Africa", "Binding", "Biological", "COVID-19", "COVID-19 pandemic", "COVID-19 patient", "COVID-19 survivors", "Case Fatality Rates", "Cessation of life", "Clinical", "Communities", "Computational algorithm", "Country", "Data Set", "Development", "Disease", "Disease Marker", "Disease Outbreaks", "Ebola", "Ebola Hemorrhagic Fever", "Ebola virus", "Epidemic", "Future", "Genetic", "Goals", "Healthcare", "Hospitals", "Human", "Immunologics", "Immunotherapeutic agent", "Individual", "Infection", "Infrastructure", "Integration Host Factors", "Investigation", "Lassa Fever", "Lassa virus", "Lead", "Measurement", "Medicine", "Mission", "Molecular", "Outcome", "Outcomes Research", "Patient-Focused Outcomes", "Patients", "Persons", "Physiological", "Play", "Research", "Research Infrastructure", "Resistance", "Role", "Severities", "Statistical Models", "Survivors", "Symptoms", "System", "Systems Biology", "Technology", "Vaccines", "Viral", "Viral Hemorrhagic Fevers", "Virus", "Work", "cohort", "coronavirus disease", "data access", "data tools", "fighting", "human disease", "human pathogen", "innovation", "insight", "large scale data", "member", "microbial", "neutralizing antibody", "novel", "pathogen", "personalized medicine", "predictive marker", "predictive modeling", "programs", "public health relevance", "response", "treatment strategy" ], "approved": true } }, { "type": "Grant", "id": "6802", "attributes": { "award_id": "5U19AI142759-04", "title": "Project 1 - Coronavirus", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [], "start_date": "2019-03-07", "end_date": "2024-02-29", "award_amount": 937500, "principal_investigator": { "id": 6340, "first_name": "MARK R.", "last_name": "DENISON", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 612, "ror": "https://ror.org/008s83205", "name": "University of Alabama at Birmingham", "address": "", "city": "", "state": "AL", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 612, "ror": "https://ror.org/008s83205", "name": "University of Alabama at Birmingham", "address": "", "city": "", "state": "AL", "zip": "", "country": "United States", "approved": true }, "abstract": "Zoonotic coronaviruses (CoVs) such as SARS-CoV and MERS-CoV are pandemic threats. MERS-CoV continues to cause new zoonotic and human transmission and illness with ~35% mortality. Currently, there are no FDA-approved therapies to treat any CoV. New zoonotic CoVs likely will emerge from heterogeneous virus pools in animal reservoirs, thus requiring antiviral strategies aimed at completely conserved and vulnerable targets. CoVs rapidly select for resistance to multiple classes of inhibitors, demonstrating the need for approaches to prevent resistance emergence. Both SARS and MERS infections manifest as severe immunopathologic damage, potentially limiting the therapeutic window for direct-acting antivirals (DAAs). Immunomodulation in the absence of antivirals has been shown to not be beneficial and to even exacerbate SARS and MERS disease. Thus, combinations of DAAs and targeted immunomodulators may be necessary for effective treatment of established infection. The overall goal of our program is to develop CoV antiviral strategies that broadly inhibit known and future potential pandemic zoonotic CoVs, prevent emergence of resistance, and extend the therapeutic window by targeting host immunopathologic responses. The proposed research will advance preclinical development of the CoV-inhibitory nucleoside analogue EIDD- 1931/2801 and other nucleoside analogues in the pipeline and test two small-molecule hits identified as highly active against SARS-CoV for treatment and prevention of epidemic and pre-emergent CoVs. In Specific Aim 1, the spectrum of antiviral activity and therapeutic efficacy of compounds will be defined. The antiviral efficacy, metabolism, and cytotoxicity of each compound will be determined in cultures of primary human lung cells targeted by SARS-CoV and MERS-CoV. The prophylactic and therapeutic efficacy of lead compounds will be evaluated in young, aged, and immunosuppressed murine models of SARS and MERS pathogenesis. In Specific Aim 2, the mechanism of action of lead compounds and kinetics of drug resistance will be determined. The antiviral effect of compounds on virus replication, fidelity, and induction of innate immunity will be assessed. Resistance mutations in genomes of MERS-CoV and SARS-CoV passaged in the presence of increasing concentrations of drug will be determined by deep sequencing. The impact of resistance on SARS-CoV and MERS- CoV virulence, sensitivity to other drugs, and therapeutic efficacy of lead compounds will be determined. Specific Aim 3 will focus on the development of combination regimens for the treatment of emerging CoVs. The combined therapeutic efficacy of DAAs against infections with both wild-type and drug-resistant SARS-CoV and MERS-CoV will be defined using cultured cells and mice. The therapeutic effect of treatment combining a DAA with an immunomodulator will be assessed in mouse models of SARS and MERS. These studies will generate mechanistic and efficacy data necessary for IND filing and origination of human clinical trials.", "keywords": [ "Acute", "Acute Respiratory Distress Syndrome", "Address", "Animals", "Antiviral Agents", "Antiviral resistance", "Cell Culture Techniques", "Cells", "Clinical Trials", "Combined Modality Therapy", "Coronavirus", "Cultured Cells", "Data", "Development", "Disease", "Drug Kinetics", "Drug resistance", "Epidemic", "Evaluation", "Exons", "Exoribonucleases", "FDA approved", "Future", "Genome", "Goals", "Human", "Immunomodulators", "In Vitro", "Infection", "Innate Immune Response", "Institutes", "Lead", "Lung", "Lung diseases", "Medical", "Metabolism", "Middle East Respiratory Syndrome", "Middle East Respiratory Syndrome Coronavirus", "Mus", "Mutagens", "Natural Immunity", "Pathogenesis", "Pathogenicity", "Pathology", "Pharmaceutical Preparations", "Prevention", "RNA", "RNA Viruses", "RNA-Directed RNA Polymerase", "Research", "Resistance", "Resistance development", "SARS coronavirus", "Science", "Severe Acute Respiratory Syndrome", "Testing", "Therapeutic", "Therapeutic Effect", "Treatment Efficacy", "Treatment Protocols", "Virulence", "Virus", "Virus Replication", "Work", "Zoonoses", "aged", "airway epithelium", "anti-viral efficacy", "antiviral nucleoside analog", "coronavirus antiviral", "coronavirus disease", "coronavirus treatment", "cytotoxicity", "deep sequencing", "drug development", "drug discovery", "drug efficacy", "effective therapy", "efficacy evaluation", "fitness", "immunoregulation", "immunosuppressed", "in vivo", "inhibitor/antagonist", "mortality", "mouse model", "novel", "novel coronavirus", "nucleoside analog", "pandemic disease", "pathogenic virus", "preclinical development", "prevent", "programs", "prophylactic", "remdesivir", "research clinical testing", "resistance mutation", "respiratory infection virus", "response", "screening", "small molecule", "therapeutically effective", "tool", "transmission process", "viral RNA", "viral fitness", "zoonotic coronavirus" ], "approved": true } }, { "type": "Grant", "id": "9038", "attributes": { "award_id": "5U19AI149504-02", "title": "Modulation of repopulation of anti HIV-1 gene-modified cells to enhance efficacy and safety", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [], "start_date": "2020-05-07", "end_date": "2025-04-30", "award_amount": 466659, "principal_investigator": { "id": 22355, "first_name": "Dong Sung SUNG", "last_name": "An", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 818, "ror": "", "name": "UNIVERSITY OF CALIFORNIA LOS ANGELES", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 818, "ror": "", "name": "UNIVERSITY OF CALIFORNIA LOS ANGELES", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Project 3: Summary/Abstract The overall goal of Project 3 is to modulate the levels of anti-HIV-1 chimeric antigen receptor (CAR) and broadly neutralizing antibodies (bNAb) modified immune cells by developing the most effective and safe positive and negative selection strategy to (1) achieve a therapeutic level of repopulation and (2) incorporate a safety “kill-switch” to eliminate the genetically engineered anti-HIV-1 immune effector cells in cases of unexpected adverse effects, such as cytokine storm, autoimmune reaction and malignant transformation. The hematopoietic stem cell-based gene therapy approach has shown great promise to achieve an HIV-1 cure. However, one of the major limitations has been the difficulty of achieving the engraftment levels sufficient to provide therapeutic efficacy, in particular for HIV-1 infected patients where intensive myeloablative conditionings would be an unfavorable risk-benefit. Thus, a safe and titratable positive selection strategy is highly desirable to maximize the level of anti-HIV-1 gene engineered immune cells to treat patients with HIV-1 without dangerous intensive myeloablation. Furthermore, it is important to incorporate a safety “kill-switch” procedure to eliminate the genetically engineered anti-HIV-1 immune effector cells based on lessons learned from severe adverse effects in cancer immunotherapy. Therefore, we will develop a negative selection strategy as a safety “kill-switch” to eliminate genetically engineered immune cells. We will identify the most effective and safe selection strategy from (1) knocking down hypoxanthine-guanine phosphoribosyltransferase (HPRT) expression using RNA interference that enables us to effectively enrich or eliminate anti-HIV-1 gene-modified HSPC using clinically available prodrug 6-thioguanine or methotrexate, (2) co-expressing truncated non-functional human epidermal growth factor receptor (huEGFRt), a cell surface marker for a rapid ex vivo positive selection and in vivo negative selection by an FDA-approved anti-EGFR monoclonal antibody Cetuximab (Erbitux) and (3) the P140K mutant form of human O6-methylguanine-DNA-methyltransferase (MGMTP140K) for a positive selection. We hypothesize that a clinically relevant, safe and effective positive and negative selection strategy can be developed by rigorously evaluating our proposed selection strategies for our anti-HIV-1 CAR and scFv-Fc bNAb combining therapies to achieve a cure of HIV disease.", "keywords": [ "Adverse effects", "Antigens", "Autoimmune", "B-Lymphocytes", "Benefits and Risks", "Bone Marrow Purging", "CAR T cell therapy", "CD19 gene", "Cell Count", "Cell surface", "Cells", "Cellular Immunity", "Cetuximab", "Clinical", "Clinical Trials", "Collaborations", "Comparative Study", "Dangerousness", "Disease", "Effector Cell", "Engineered Gene", "Engraftment", "Epidermal Growth Factor Receptor", "Erbitux", "FDA approved", "Gene Delivery", "Gene-Modified", "Genetic Engineering", "Goals", "HIV", "HIV-1", "Hematopoietic stem cells", "Human", "Humoral Immunities", "Hypoxanthine Phosphoribosyltransferase", "Immune", "In Vitro", "Investigational New Drug Application", "Lentivirus Vector", "MGMT gene", "Macaca nemestrina", "Malignant - descriptor", "Malignant Neoplasms", "Methotrexate", "Modeling", "Mus", "Patients", "Procedures", "Prodrugs", "RNA Interference", "Reaction", "Risk", "Safety", "T-Lymphocyte", "Testing", "Therapeutic", "Thioguanine", "TimeLine", "Toxic effect", "Transplantation", "Treatment Efficacy", "Virus Replication", "base", "cancer immunotherapy", "chimeric antigen receptor", "chimeric antigen receptor T cells", "clinically relevant", "cytokine release syndrome", "gene therapy", "immunoengineering", "immunogenicity", "in vivo", "knock-down", "mutant", "neutralizing antibody", "nonhuman primate", "preclinical development", "programs" ], "approved": true } } ], "meta": { "pagination": { "page": 1384, "pages": 1424, "count": 14236 } } }