Grant List
Represents Grant table in the DB
GET /v1/grants?sort=-start_date
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-start_date", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1424&sort=-start_date", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=2&sort=-start_date", "prev": null }, "data": [ { "type": "Grant", "id": "15946", "attributes": { "award_id": "1R01AI196117-01", "title": "Advancing Analytical Tools to Quantify and Mitigate the Risk for Transitioning from Episodic to Endemic Transmission for Emerging 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": 32873, "first_name": "MISRAK", "last_name": "GEZMU", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-10", "end_date": "2031-03-31", "award_amount": 787837, "principal_investigator": { "id": 26281, "first_name": "Seth", "last_name": "Blumberg", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3405, "ror": "", "name": "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "This project will develop and apply computational tools for assessing the risk that diseases with episodic transmission become established in the general population. Our project is relevant to emerging zoonoses, re-emerging vaccine-preventable diseases, and healthcare-associated infections. Timely identification and control of such diseases could have significantly altered the course of mpox, SARS-CoV-2, and antimicrobial resistance. It is therefore important to have methods available to monitor and fully elucidate the transmission patterns of infectious diseases that can develop increased burden through pathogen evolution, reduced population immunity, or other sociodemographic changes. Any such method needs to consider patchy surveillance and differences in risk among those who are exposed to the disease. Furthermore, diseases that cause episodic outbreaks might require specific control strategies that are different from those that apply to epidemic or endemic diseases. Existing models that explore some of these aspects typically omit key factors, rely on untested assumptions, or are validated in a circular fashion using simulations based on the same assumptions they aim to test. This limits their reliability for real-world applications. To address this gap, we will combine statistical inference with simulation approaches to address key questions in quantifying and mitigating the risk from infectious diseases. We will extend methods for inference using branching process models to take into account imperfect observations and heterogeneity in both transmission and susceptibility. We will apply these methods to a range of applications to improve our ability to learn from data describing sporadic infection clusters. We will also use mobility and demographic data to construct synthetic populations representing situations where infections cause occasional outbreaks. This will permit stress-testing of inference methods and evaluation of control strategies. Our iterative approach will allow us to refine model assumptions, improve inference robustness, and identify the most informative data types for public health surveillance and control. The work will result in a greater understanding of how public health agencies can best use data from episodic disease transmission and computational tools for applying this understanding to coming threats. To demonstrate the breadth of applicability, we will apply our methodological advancements to (1) quantify the transmissibility of H5N1 influenza, (2) determine the probability of large measles outbreaks occurring annually, and (3) evaluate control strategies for reducing transmission of virulent, healthcare-associated MRSA strains. To promote scientific reproducibility, we will produce user-friendly software that integrates with existing packages and share synthetic population data. Our team is well-positioned to conduct this work since we have developed many existing tools and paradigms for analyzing episodic transmission, including branching process models and outbreak simulations in synthetic populations. By advancing the science of disease transmission and equipping public health agencies with actionable results, this work will reduce the risk of future pandemics.", "keywords": [ "2019-nCoV", "Address", "Antimicrobial Resistance", "Behavior", "COVID-19 pandemic", "California", "Cations", "Clinical Data", "Communicable Diseases", "Communities", "County", "Data", "Data Collection", "Disease", "Disease Outbreaks", "Effectiveness", "Emerging Communicable Diseases", "Emerging infection", "Endemic Diseases", "Epidemic", "Epidemiology", "Evaluation", "Evolution", "Exhibits", "Exposure to", "Future", "General Population", "Goals", "Health Care", "Heterogeneity", "Household", "Human", "Immunity", "Individual", "Infection", "Influenza", "Influenza A Virus H5N1 Subtype", "Intervention", "Learning", "Link", "Measles", "Methodology", "Methods", "Modeling", "Modernization", "Monitor", "Monkeypox", "Pattern", "Population", "Population Surveillance", "Positioning Attribute", "Predisposition", "Probability", "Process", "Public Health", "Reproducibility", "Reproduction", "Research", "Resources", "Risk", "Risk Assessment", "Risk Reduction", "Route", "Science", "Statistical Methods", "Stress Tests", "Structure", "Study models", "Techniques", "Testing", "United States", "Vaccines", "Virulent", "Work", "Zoonoses", "advanced analytics", "analytical tool", "computerized tools", "data streams", "disease transmission", "disorder control", "disorder risk", "evidence base", "future pandemic", "generative artificial intelligence", "health care associated infections", "improved", "innovation", "mathematical model", "methicillin resistant Staphylococcus aureus", "model development", "models and simulation", "novel", "pathogen", "predicting response", "prevent", "previous pandemic", "public health intervention", "real world application", "risk mitigation", "simulation", "sociodemographics", "synthetic construct", "tool", "transmission process", "user friendly software" ], "approved": true } }, { "type": "Grant", "id": "15958", "attributes": { "award_id": "1R01AI190181-01A1", "title": "Advancing iPSC-derived Thymic Epithelial Cells as Cell Therapy for T Cell Immune Reconstitution in Vulnerable Populations(original application ID AI190181-01)", "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": 44292, "first_name": "MERCY R", "last_name": "PRABHUDAS", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-08", "end_date": "2031-03-31", "award_amount": 809250, "principal_investigator": { "id": 44405, "first_name": "Katja Gabriele", "last_name": "Weinacht", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3414, "ror": "", "name": "STANFORD UNIVERSITY", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "| NARRATIVE The thymus instructs T cell immunity and central tolerance, yet its therapeutic potential remains clinically untapped as the signals that drive thymic epithelial cell (TEC) differentiation remain incompletely understood. The thymic epithelium comprises a highly specialized set of cells that attract lymphoid progenitors, promote their proliferation and maturation into thymocytes, and facilitate the selection of a diverse, self-tolerant T cell receptor (TCR) repertoire. The role of the thymus in building immune identity begins before birth. The organ peaks in size in infancy and then structurally and functionally involutes over time. This process causes the decline in immune competence with age (immune senescence). The impact of this phenomenon was exposed during the COVID-19 pandemic when waning immunity left the elderly more vulnerable to adverse outcomes. Thymus insult also occurs in many patients through medications, radiation, infections and graft-versus-host disease. The most severe form of thymic compromise is congenital athymia, the inborn absence of the thymus due to genetic mutations. Genetic or acquired thymic injury leads to immunodeficiency, autoimmunity, inflammation and increased cancer risk. Regenerating thymic function, e.g., through human induced pluripotent stem cell (iPSC)-derived regenerative thymic tissues holds greatest therapeutic promise for these patients. We have used single-cell transcriptomics of human fetal anterior foregut-derived organs to uncover the signals that drive TEC differentiation. We have translated these insights into a novel differentiation platform for the derivation of TECs from iPSCs in vitro. When iPSC-derived TEC organoids are transplanted into athymic NSG nude (NSG-Foxn1-/-) mice engrafted with human hematopoietic stem cells, they function like the human thymus, giving rise to human ab-T cells with a diverse TCR repertoire, gd-T cells and regulatory T cells. In this application, we now seek to advance the translation of iPSC-derived TECs (iTECs) by testing their safety and efficacy as cell therapy for vulnerable patient populations in need of improved T cell immunity. In Aim 1, we will determine the capacity of iTECs to promote T cell reconstitution, functional antigen-specific T cell responses and the development of a broad TCR repertoire in vivo. In Aim 2, we will assess if T cells educated on iTEC are tolerant to “self” but respond to “non-self”. In addition, we will directly analyze the HLA-associated peptide repertoire presented on iTECs using immunopeptidomics. In Exploratory Aim 3, we will test if HLA-editing of iPSCs for iTECs derivation affects antigen-specific immune responses, TCR repertoire, and immunopeptidome in vivo. Advancing the translation of iPSC-derived TECs into a cell therapy is an entirely new strategy to leverage the therapeutic potential of T cells from inside the body and could begin a new chapter of immunotherapeutics.", "keywords": [ "Affect", "Age", "Aging", "Allogenic", "Anterior", "Antibody Response", "Antigens", "Autoimmunity", "Birth", "CD8B1 gene", "COVID-19 pandemic", "Cancer Vaccines", "Cell Differentiation process", "Cell Maintenance", "Cell Physiology", "Cell Therapy", "Cells", "Child", "Clinical", "Defect", "Derivation procedure", "Development", "Elderly", "Engraftment", "Epithelium", "Future", "Genetic", "Genetic Transcription", "Goals", "Hematopoietic Stem Cell Transplantation", "Hematopoietic stem cells", "Histocompatibility", "Histologic", "Human", "Immune", "Immune response", "Immune system", "Immunity", "Immunocompetence", "Immunocompromised Host", "Immunosuppression", "Immunotherapeutic agent", "Immunotherapy", "In Vitro", "Infant", "Infection", "Inflammation", "Injury", "Interferons", "Lead", "Left", "Life", "Malignant Neoplasms", "Medical", "Mixed Lymphocyte Culture Test", "Mus", "Mutation", "Natural regeneration", "Nude Mice", "Organ", "Organ Donor", "Organ Transplantation", "Organoids", "Output", "Pathogenicity", "Patients", "Peptides", "Pharmaceutical Preparations", "Population", "Primitive foregut structure", "Process", "Prognosis", "Proliferating", "Radiation", "Regulatory T-Lymphocyte", "Rejuvenation", "Role", "Safety", "Self Tolerance", "Signal Transduction", "Solid", "T cell reconstitution", "T cell response", "T cell therapy", "T-Cell Development", "T-Lymphocyte", "T-cell receptor repertoire", "Testing", "Tetanus", "Therapeutic", "Thymic Tissue", "Thymic epithelial cell", "Thymus Gland", "Time", "Translating", "Translations", "Transplantation", "Vulnerable Populations", "Work", "adverse outcome", "antigen-specific T cells", "athymia", "cancer risk", "central tolerance", "differentiation protocol", "efficacy evaluation", "efficacy testing", "engineered T cells", "fetal", "graft vs host disease", "human data", "human induced pluripotent stem cells", "human leukocyte antigen testing", "immune checkpoint blockade", "immune reconstitution", "immunodeficiency", "immunosenescence", "improved", "in vivo", "induced pluripotent stem cell", "infancy", "insight", "lymphoid progenitors", "novel", "novel strategies", "organoid transplantation", "pandemic disease", "patient population", "prevent", "regenerative", "response", "risk mitigation", "stem cell derived tissues", "technology platform", "thymic aplasia", "thymic regeneration", "thymocyte", "transcriptomics" ], "approved": true } }, { "type": "Grant", "id": "15957", "attributes": { "award_id": "1R01AI196011-01", "title": "Protective mRNA Vaccines Against Tuberculosis", "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": 44404, "first_name": "KATRIN", "last_name": "EICHELBERG", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-06", "end_date": "2031-03-31", "award_amount": 717003, "principal_investigator": { "id": 27480, "first_name": "ADEL M", "last_name": "TALAAT", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 799, "ror": "", "name": "UNIVERSITY OF WISCONSIN-MADISON", "address": "", "city": "", "state": "WI", "zip": "", "country": "United States", "approved": true }, "abstract": "Protective mRNA Vaccines Against Tuberculosis. Summary. Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), remains a significant global health challenge, affecting approximately one-third of the world’s population and resulting in nearly 1.4 million deaths annually. The existing vaccine, M. bovis BCG (BCG), offers variable protection, with efficacy ranging from 0% to 80%. Our previous research has identified several innovative platform technologies aimed at enhancing vaccine development for major infections impacting both human and animal health. Notably, we have developed unique nano-adjuvant systems (NAS) that have demonstrated effectiveness against respiratory infections, including coronavirus and M. avium. In this project, we will utilize our expertise in tuberculosis vaccine development and nanoparticle vaccine platforms to assess the protective efficacy of a novel combination vaccine against TB. Our approach incorporates cutting-edge mRNA vaccine technology delivered via QuilA-DOTAP (QTAP), a novel lipid nanoparticle delivery adjuvant that ensures stable mRNA transcript delivery at various temperatures suitable for use in TB- endemic regions. Preliminary analyses of QTAP-adjuvanted combination mRNA vaccine encoding three mycobacterial antigens (Ag85B, Hsp70, and EsxH), referred to as QRNA, have shown robust protective immunity in mouse models challenged with both low and high doses of the virulent M. tb Erdman strain. In this project, we plan to First; examine the safety and immunogenicity of QRNA vaccines in variable murine models using both immune-compromised (Rag1-/-) and immune-competent (C3HeB/FeJ) murine models. Second; analyze the protective role of QRNA vaccine as a homologous or heterologous vaccine primed with BCG against challenge with M. tb Erdman (lineage 4, laboratory strain) or HN878 (lineage 2, hypervirulent clinical strain). Finally, we will assess protective immunity of QRNA vaccines in guinea pigs to identify vaccine-induced immune correlates of protection elicited by the mRNA vaccine candidates in guinea pigs, a TB model that mimic human infection. Once achieved, results from those aims will enhance our understanding of RNA-based immunization against TB. Future projects will further dissect the generated immunity in non-human primates, a more relevant model for human TB.", "keywords": [ "Address", "Adjuvant", "Adopted", "Adult", "Aerosols", "Affect", "Animals", "Antigens", "Area", "BCG Vaccine", "Bacille Calmette-Guerin vaccination", "C3HeB/FeJ Mouse", "CD8B1 gene", "Categories", "Cavia", "Cells", "Cessation of life", "Clinical", "Combined Vaccines", "Coronavirus", "Developing Countries", "Development", "Disease", "Disease Outbreaks", "Dose", "Effectiveness", "Emerging infection", "Ensure", "Flow Cytometry", "Future", "Generations", "Health", "Human", "IL17 gene", "Immune", "Immune response", "Immunity", "Immunization", "Immunocompetent", "Infection", "Interferon Type II", "Interleukin-2", "Laboratories", "Maps", "Messenger RNA", "Modeling", "Mus", "Mycobacterium Infections", "Mycobacterium avium", "Mycobacterium bovis", "Mycobacterium tuberculosis", "Outcome", "Outcomes Research", "Pathology", "Population", "Public Health", "RNA", "RNA vaccination", "RNA vaccine", "Rag1 Mouse", "Regimen", "Research", "Respiratory Tract Infections", "Rodent Model", "Role", "Safety", "System", "T-Lymphocyte", "TNF gene", "Technology", "Temperature", "Tissues", "Transcript", "Tuberculosis", "Tuberculosis Vaccines", "United States National Institutes of Health", "Vaccination", "Vaccines", "Virulent", "authority", "cytokine", "global health", "immunogenicity", "improved", "innovation", "lipid nanoparticle", "mRNA Stability", "mouse model", "mycobacterial", "nano", "nanoparticle", "nanoparticle delivery", "nonhuman primate", "novel", "protective efficacy", "technology platform", "transcriptome sequencing", "transcriptomic profiling", "tuberculosis immunity", "vaccine candidate", "vaccine development", "vaccine formulation", "vaccine immunogenicity", "vaccine platform", "vaccine safety" ], "approved": true } }, { "type": "Grant", "id": "15944", "attributes": { "award_id": "1R01AI195454-01", "title": "Hijacking the neonatal Fc receptor: the novel biology of arterivirus entry, transmission, and persistence", "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": 44307, "first_name": "RODOLFO M", "last_name": "ALARCON", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-03", "end_date": "2031-03-31", "award_amount": 615446, "principal_investigator": { "id": 31459, "first_name": "Adam Lee", "last_name": "Bailey", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3403, "ror": "", "name": "UNIVERSITY OF WISCONSIN-MADISON", "address": "", "city": "", "state": "WI", "zip": "", "country": "United States", "approved": true }, "abstract": "Understanding novel mechanisms by which animal viruses enter cells, evade immunity, and cause disease has scientific and public health importance. Arteriviruses are an understudied family of RNA viruses (related to coronaviruses) that infect a wide variety of mammals. The host and viral factors that determine arterivirus disease, persistence, and cross-species transmission remain unknown and unpredictable. This lack of understanding has implications for predicting/thwarting arterivirus emergence in humans, as some arteriviruses have been shown to infect human cells. Macrophages are exclusively infected by most arteriviruses, but the subpopulation(s) of macrophages that support arterivirus replication remain poorly defined. The process by which arteriviruses enter cells is highly novel and also poorly understood. Each virion displays an unusually large set of surface glycoproteins (7-11 depending on the virus) that are unlike any known viral fusion machinery. The macrophage-specific molecule CD163 is a required arterivirus receptor, yet CD163 by itself is insufficient to mediate arterivirus entry. We recently identified the neonatal Fc receptor (FcRn) as an important entry factor that arteriviruses use together with CD163 to gain entry into cells. Aim 1 of this project builds upon this discovery to define the molecular details of the arterivirus:FcRn interaction. In Aim 1a, we will map the site(s) on FcRn that are critical for arterivirus engagement by creating chimeric FcRn molecules that incorporate features of arterivirus-permissive and -resistant FcRn orthologs, with the goal of defining the domains, motifs, and residues involved in arterivirus/FcRn interactions. In Aim 1b, we will generate chimeric arteriviruses that contain combinations of glycoproteins from different arteriviruses, seeking to define the viral glycoproteins, domains, motifs, and residues involved in FcRn engagement. In Aim 1c, we will continue to develop our understanding of the host factors required for arterivirus entry by performing screens to identify additional host factors that are functionally redundant with FcRn for the viral entry process. In Aim 2, we will use the murine arterivirus (lactate dehydrogenase-elevating virus, LDV), which causes life-long viremia in adult mice, to understand several aspects of arterivirus infection in vivo. In Aim 2a, we will use a nanoluciferase-expressing LDV to perform body-wide imaging and identify the tissues that support LDV infection over time. In Aim 2b, we will hone in key tissues and identify the macrophage populations within these tissues that support LDV infection and determine how persistent arterivirus infection impacts recovery of target cell populations. Finally, in Aim 2c we will use FcRn-knockout mice to determine whether arteriviruses hijack FcRn’s physiologic role in placental biology, potentially explaining the high efficiency with which arteriviruses transmit vertically. This project will provide insights into novel mechanisms of viral entry, macrophage infection and dysfunction, viral persistence, and vertical transmission through the study of the neglected “pre-emergent” family of mammalian viruses, the arteriviruses.", "keywords": [ "Acute", "Acute Disease", "Adult", "Anatomy", "Animals", "Arterivirus", "Arterivirus Infections", "Biology", "Cell Culture Techniques", "Cell Line", "Cell Surface Receptors", "Cells", "Clustered Regularly Interspaced Short Palindromic Repeats", "Complex", "Coronavirus", "Development", "Disease", "Distant", "Family", "Family suidae", "Farm", "Fc Receptor", "Fetus", "Functional disorder", "Glycoproteins", "Goals", "Human", "Image", "Immune system", "Immunity", "Immunoglobulin G", "Industry", "Infection", "Integration Host Factors", "Knock-out", "Knockout Mice", "Knowledge", "Laboratories", "Lactate dehydrogenase-elevating virus", "Life Cycle Stages", "Link", "Macrophage", "Mammals", "Maps", "Mediating", "Membrane Glycoproteins", "Modeling", "Molecular", "Mus", "Orthologous Gene", "Phase", "Physiological", "Placenta", "Placental Biology", "Pneumonia", "Population", "Positioning Attribute", "Predisposition", "Primates", "Process", "Public Health", "RNA Viruses", "Recovery", "Reporter", "Research", "Resistance", "Retinal blind spot", "Role", "Site", "Structure", "Surface", "Syncytiotrophoblast", "System", "Time", "Tissues", "Tropism", "Vertical Transmission", "Viral", "Viral Hemorrhagic Fevers", "Viremia", "Virion", "Virus", "Virus Receptors", "Virus Replication", "Whole Organism", "cell immortalization", "chronic infection", "cross-species transmission", "economic impact", "fetal", "genome-wide", "in utero", "in vivo", "insight", "medical countermeasure", "model organism", "nanoluciferase", "neglect", "neonatal Fc receptor", "novel", "permissiveness", "pregnant", "receptor", "reverse genetics", "time use", "transmission process" ], "approved": true } }, { "type": "Grant", "id": "15952", "attributes": { "award_id": "1K25AI196259-01", "title": "Modeling SARS-CoV-2 variant emergence from immunocompromised hosts", "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": 32891, "first_name": "MARY KATHERINE BRADFORD", "last_name": "PLIMACK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-02", "end_date": "2031-03-31", "award_amount": 161946, "principal_investigator": { "id": 44397, "first_name": "Katherine", "last_name": "Owens", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3410, "ror": "", "name": "FRED HUTCHINSON CANCER CENTER", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "This proposal describes a five-year research training program that will facilitate my ongoing transition from an applied mathematician to an independent, quantitative, multidisciplinary biomedical researcher. I will work closely with clinicians, mathematical modelers, bioinformaticians, evolutionary biologists, virologists and immunologists to develop a suite of mathematical models which will be validated against viral, immune, phylogenetic and epidemiolocal datasets. The goals of my proposal will be to: 1) understand the mechanisms facilitating generation of SARS-CoV-2 variants of concern (VOC) during prolonged infections in immunocompromised (IC) individuals, and 2) identify key bottle necks that limit the number of VOCs that predominate in the general population. SARS-CoV-2 is the appropriate virus for which to develop this modeling framework due to the availability of data, and ongoing incidence, but the approach will be widely applicable to other pathogens. The training program includes an outstanding group of mentors and collaborators. My scientific advisory committee consists of experts in modeling infectious diseases (Dr Josh Schiffer and Dr Dan Reeves), clinical care for IC individuals (Dr Josh Schiffer and Dr. Alpana Wahgmare), epidemiology (Dr Cheryl Cohen and Dr Dobromir Dimitrov), viral evolution (Dr JT McCrone and Dr Mahan Ghafari), and biostatistics and machine learning (Dr Ollivier Hyrien). This group is dedicated to ensuring the success of my project, and my career development as an independent researcher. The specific learning goals required for my successful transition to biomedical research will be accomplished through didactic coursework in virology, immunology, epidemiology and phylogenetics as well as conferences and professional training in the skills of a successful mentor and group leader. The research plan addresses a critically important clinical and public health issue. Prolonged SARS-CoV- 2 infections in IC individuals are the most likely source of most novel VOC, which have extended and strongly exacerbated the impact of the pandemic. Though these infections have had an outsized public health impact, clear guidance regarding clinical management and safety measures is lacking. Understanding the within-host evolution of SARS-CoV-2 is paramount to addressing these issues. Through accomplishing the aims of this proposal, Dr Owens will address critical gaps in our knowledge of SARS-CoV-2 evolution and create an in silico framework to study SARS-CoV-2 interventions at both individual and population level. Ultimately, this proposal will allow Dr Owens to influence the future of pandemic response research as well as build a self-sustaining program at the interface of mathematical modeling, immunology, viral dynamics, and viral evolution.", "keywords": [ "2019-nCoV", "Address", "Advisory Committees", "Aftercare", "Anatomy", "Award", "Biomedical Research", "Biometry", "COVID-19 impact", "COVID-19 incidence", "Calibration", "Cessation of life", "Clinical", "Clinical Management", "Clinical Trials", "Data", "Data Set", "Dedications", "Effectiveness of Interventions", "Ensure", "Epidemiology", "Evolution", "Frequencies", "General Population", "Generations", "Genetic", "Genetic Drift", "Genetic Recombination", "Goals", "Guidelines", "Health Policy", "Heterogeneity", "Immune", "Immune response", "Immunity", "Immunocompromised Host", "Immunologics", "Immunologist", "Immunology", "Incidence", "Individual", "Infection", "Intervention", "Kinetics", "Knowledge", "Learning", "Link", "Machine Learning", "Mathematics", "Measures", "Mentors", "Mentorship", "Modeling", "Mutate", "Mutation", "Neck", "Nucleotides", "Output", "Pattern", "Phylogenetic Analysis", "Population", "Program Sustainability", "Public Health", "Published Comment", "Recording of previous events", "Research", "Research Personnel", "Research Training", "Risk", "Risk Factors", "SARS-CoV-2 infection", "SARS-CoV-2 variant", "Safety", "Scientist", "Social Distance", "Source", "Testing", "Training", "Training Programs", "United States National Institutes of Health", "Vaccination", "Variant", "Viral", "Viral Genes", "Viral Load result", "Virus", "Virus Replication", "Work", "career", "career development", "chronic infection", "clinical care", "community transmission", "design", "epidemiologic data", "experience", "fitness", "future pandemic", "immunological status", "in silico", "ineffective therapies", "infectious disease model", "insight", "machine learning method", "mathematical model", "multidisciplinary", "novel", "pandemic impact", "pandemic preparedness", "pandemic response", "pathogen", "patient oriented", "pressure", "skills", "success", "symposium", "tool", "transmission process", "vaccine distribution", "variants of concern", "viral rebound", "virology" ], "approved": true } }, { "type": "Grant", "id": "15953", "attributes": { "award_id": "1K08AI196260-01", "title": "Human upper airway immune memory kinetics and durability against respiratory pathogens", "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": 32599, "first_name": "MICHELLE MARIE", "last_name": "ARNOLD", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-02", "end_date": "2031-03-31", "award_amount": 159300, "principal_investigator": { "id": 44398, "first_name": "Sydney Ilima", "last_name": "Ramirez", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3411, "ror": "", "name": "LA JOLLA INSTITUTE FOR IMMUNOLOGY", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Peripheral blood is the primary sample type collected to evaluate a vast range of medical conditions. However, peripheral blood testing may not reflect processes occurring in tissue, like the upper airway. The SARS- CoV-2 (SARS2) pandemic highlighted the importance of being able to sample the upper airway for purposes including evaluation of viral infection and clearance. Although the upper airway represents the primary site of infection for many human pathogens, critical questions remain regarding upper airway immunity and protection. Nasal cavity swab sampling can be used to bridge knowledge gaps regarding upper airway immunity to important respiratory pathogens like SARS2 and to address important immunologic questions where peripheral blood sampling is inherently insufficient. I established novel methods for reproducible, longitudinal sampling of upper airway immune cell populations using swabs and demonstrated that sufficient numbers of viable immune cells could be collected to allow for high resolution downstream analyses, including multiparametric flow cytometry and single cell RNA sequencing. Upper airway resident memory B and T cell populations, including SARS2- specific memory B and T cells were characterized using these methods. There is great interest in developing next generation vaccines, including vaccines that can elicit robust mucosal immune responses. This requires knowledge of the immunologic contexts in which mucosal immunity is generated and the requirements for maintenance of upper airway immune memory. I hypothesize that local antigen exposure is required to develop durable upper airway immune memory, and intramuscular immunization alone may fail to elicit upper airway immunity despite generating circulating immunity. I will test this hypothesis by studying upper airway memory B and T cell frequencies, diversity, kinetics and durability in distinct immunologic contexts including SARS2 breakthrough infection (BTI) and COVID-19 booster vaccination using this award. Other respiratory pathogens of public health importance will also be examined. If funded, this K08 will assist with my transition to becoming a successful independent physician scientist investigator in human immunology and infectious diseases. The La Jolla Institute for Immunology (LJI) is a superb training environment and located on the campus of another excellent academic research and medical institution, the University of California, San Diego (UCSD). I will receive ongoing mentorship from an established investigator with a track record for producing successful mentees, Professor Shane Crotty, PhD, a world- renowned expert in the field of immunology. LJI and UCSD are closely affiliated, and Dr. Crotty has an adjunct appointment at UCSD. I will have access to resources at both LJI and UCSD for this career development award. As an Associate Physician in UCSD’s Division of Infectious Diseases I will receive additional mentorship in academic career development, and maintain my clinical acumen by providing part-time medical care and consultation services for medically complex patients.", "keywords": [ "2019-nCoV", "Address", "Adult", "Animal Model", "Antibodies", "Antibody Response", "Antibody titer measurement", "Antigens", "Appointment", "Award", "B-Lymphocytes", "Blood Tests", "Blood specimen", "CD8-Positive T-Lymphocytes", "COVID-19 booster", "COVID-19 pandemic", "COVID-19 vaccination", "California", "Caring", "Cell Survival", "Cell secretion", "Cells", "Clinical", "Common Cold", "Communicable Diseases", "Complex", "Consultations", "Coronavirus", "Coronavirus Infections", "Data", "Development", "Disease", "Doctor of Philosophy", "Enrollment", "Environment", "Epitopes", "Evaluation", "Flow Cytometry", "FluMist", "Frequencies", "Funding", "Human", "Immune", "Immunity", "Immunization", "Immunoglobulin A", "Immunologic Memory", "Immunologics", "Immunology", "Immunophenotyping", "Infection", "Infection Control", "Infection prevention", "Influenza", "Institution", "Intramuscular", "Investigation", "K-Series Research Career Programs", "Kinetics", "Knowledge", "Left", "Licensing", "Maintenance", "Mediating", "Medical", "Memory", "Memory B-Lymphocyte", "Mentorship", "Methods", "Morbidity", "Mucosal Immune Responses", "Mucosal Immunity", "Mucous Membrane", "Nasal cavity", "Nasal turbinate bone structure", "Nasopharynx", "Nose", "Patients", "Physicians", "Play", "Population", "Primates", "Process", "Public Health", "Reproducibility", "Research", "Research Personnel", "Resolution", "Resources", "Role", "SARS-CoV-2 exposure", "SARS-CoV-2 immunity", "SARS-CoV-2 infection", "SARS-CoV-2 variant", "Sampling", "Scientist", "Secondary Immunization", "Services", "Severity of illness", "Site", "Source", "Swab", "T cell response", "T-Cell Receptor", "T-Lymphocyte", "Testing", "Time", "Tissues", "Training", "Universities", "Vaccination", "Vaccine Design", "Vaccines", "Viral", "Virus Diseases", "acquired immunity", "adaptive immunity", "breakthrough infection", "career development", "cohort", "cross reactivity", "cytokine", "experimental study", "flu", "human pathogen", "influenza virus vaccine", "insight", "interest", "live attenuated influenza vaccine", "minimally invasive", "mortality", "mucosal vaccine", "nasopharyngeal swab", "neutralizing antibody", "novel", "novel strategies", "novel therapeutics", "novel vaccines", "pandemic disease", "peripheral blood", "professor", "respiratory pathogen", "respiratory virus", "response", "severe COVID-19", "single-cell RNA sequencing" ], "approved": true } }, { "type": "Grant", "id": "15950", "attributes": { "award_id": "1K08AI196255-01", "title": "Neutralizing antibody pressure on the evolution of SARS-CoV-2 variants.\"", "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": 32891, "first_name": "MARY KATHERINE BRADFORD", "last_name": "PLIMACK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-02", "end_date": "2031-03-31", "award_amount": 194160, "principal_investigator": { "id": 44394, "first_name": "Ian Alexander", "last_name": "Mellis", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3409, "ror": "", "name": "COLUMBIA UNIVERSITY HEALTH SCIENCES", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "/ ABSTRACT: Rationale: SARS-CoV-2 evolution has led to the emergence of viral variants that evade existing immunity in the human population, which continue to pose a threat to global public health. It has proven challenging to predict which mutations will arise in future dominant viral variants, and, as a result, it is difficult to design vaccines that provide adequate protection against viruses that will circulate in future waves of infections. Our preliminary data show that viral variant evolution is most closely correlated with evasion of serum neutralizing antibodies, and that serum neutralizing antibody responses are shaped by immune imprinting to the ancestral D614G strain. This mentored career project aims to leverage these observations to develop an in vitro model for predicting where mutations will appear in the virus and to use that information to design updated vaccines. Candidate: As a Transfusion Medicine fellow with a PhD in Genomics and Computational Biology and two years of experience in virology and immunology research, I bring a unique complement of perspectives and skills to the analysis of viral and antigenic evolution and to vaccine design strategies. Further training in advanced BSL-2-compatible pseudovirus culture, mouse immunization, and computational structural biology will be central to the completion of the proposed project and to my development as an independent physician-scientist aiming to improve our understanding and mitigation of pathogen evolution. My primary mentor, Dr. David Ho, an international leader in virology, and my complementary multidisciplinary advisory team, will ensure my research and career development progress. Environment: The Ho laboratory at the Columbia University Irving Medical Center (CUIMC) is a world leader in the study of pandemic viruses, including SARS-CoV-2, with expertise in the characterization of viral variants and serum antibody analysis. The Ho lab has access to abundant resources and many collaborators, including leaders in pseudovirus construction, structural biology, and vaccine design. CUIMC also has a long track record of supporting junior physician-scientists on their paths to successful independent careers in academic medicine. Approach: We will test the central hypothesis that widespread early exposure to ancestral SARS-CoV-2 shapes the evolutionary trajectory of the virus and that such a trajectory can be modeled in vitro. In Aim 1 we will assess the impact of mouse serum neutralizing antibodies elicited by different immunization histories on mutational profiles in cultured BSL-2-rated pseudoviruses and correlate mutations with historical public health databases. In Aim 2, we will identify whether particular epitopes on the spike protein are particularly susceptible to the emergence of mutations under serum antibody selective pressure. In Aim 3, we will design and test novel COVID-19 vaccine candidates in mice based on observed mutations that arise in pseudoviruses. This project will enhance our understanding of SARS-CoV-2, provide a framework for in vitro modeling of antigenically variable pathogens, and contribute to vaccine design strategies.", "keywords": [ "2019-nCoV", "Advisory Committees", "Antibodies", "Antibody Response", "Antigenic Variation", "Antigens", "Biological Assay", "COVID-19", "COVID-19 booster", "COVID-19 vaccine", "Cessation of life", "Complement", "Computational Biology", "Data", "Databases", "Dengue", "Development", "Doctor of Philosophy", "Ensure", "Environment", "Epitopes", "Escape Mutant", "Evolution", "Exposure to", "Formulation", "Frequencies", "Future", "Genomics", "Growth", "Human", "Immune", "Immune response", "Immunity", "Immunization", "Immunize", "Immunology", "Impairment", "In Vitro", "Individual", "Infection", "Influenza", "International", "Junior Physician", "Laboratories", "Machine Learning", "Maps", "Measures", "Medical center", "Medicine", "Mentors", "Modeling", "Monoclonal Antibodies", "Mus", "Mutation", "Physicians", "Population", "Predisposition", "Proteins", "Public Health", "RNA vaccine", "Recording of previous events", "Research", "Resolution", "Resources", "SARS-CoV-2 spike protein", "SARS-CoV-2 variant", "Scientist", "Serum", "Shapes", "Structural Models", "System", "Testing", "Training", "Universities", "Update", "Vaccination", "Vaccine Design", "Vaccines", "Variant", "Vesicular stomatitis Indiana virus", "Viral", "Viral Genome", "Virus", "Work", "booster vaccine", "candidate identification", "career", "career development", "cohort", "design", "emerging virus", "experience", "exposure mixture", "genome sequencing", "imprint", "improved", "in vitro Model", "innovation", "multidisciplinary", "mutant", "mutation screening", "neutralizing antibody", "novel", "novel vaccines", "pandemic disease", "pandemic virus", "pathogen", "predictive modeling", "pressure", "public health intervention", "recurrent infection", "research and development", "skills", "structural biology", "therapy development", "transfusion medicine", "vaccine candidate", "vaccine development", "variants of concern", "virology" ], "approved": true } }, { "type": "Grant", "id": "15947", "attributes": { "award_id": "1I01RD001550-01A1", "title": "A systems biology approach to identifying mechanisms underlying enhanced reactogenicity after mRNA-based vaccination", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2026-04-01", "end_date": "2030-03-31", "award_amount": null, "principal_investigator": { "id": 8775, "first_name": "DAVID H", "last_name": "CANADAY", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 497, "ror": "https://ror.org/051fd9666", "name": "Case Western Reserve University", "address": "", "city": "", "state": "OH", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 3406, "ror": "", "name": "LOUIS STOKES CLEVELAND VA MEDICAL CENTER", "address": "", "city": "", "state": "OH", "zip": "", "country": "United States", "approved": true }, "abstract": "Significance to the VA: Vaccine hesitancy toward COVID-19 mRNA vaccines remains a significant challenge. Identifying ways to reduce hesitancy is a key objective of these studies. Reactogenicity refers to adverse events (AEs) that occur shortly after vaccination as a physical manifestation of the inflammatory response. Understanding which reactogenic mechanisms are most closely linked to enhanced immunogenicity is crucial for designing interventions that mitigate negatively perceived side eKects without compromising the protective immune response. The veteran population includes a high proportion of older, multimorbid individuals who are particularly susceptible to severe morbidity and mortality from SARS-CoV-2 and RSV, both of which have approved mRNA vaccines, and influenza, for which an mRNA vaccine is anticipated soon. As the use of mRNA vaccine platforms increases, eKorts to facilitate their acceptance and utilization are essential for veteran health. Innovation and Impact: To our knowledge, no NIH-supported studies are investigating mRNA vaccine reactogenicity using systems biology approaches, particularly in VA priority cohorts, as indicated by NIH RePORTER and ClinicalTrials.gov. No comprehensive systems biology studies have focused on identifying specific pathways and molecules associated with AEs from mRNA vaccines. This innovative approach can help VA providers explain vaccine use and AEs, increasing uptake. Additionally, our findings could inform strategies to reduce AEs while maintaining protective immune responses. Specific Aims: Aim 1: Determine the mechanisms underlying reactogenicity by assessing local and systemic AEs following mRNA COVID-19 vaccination. Hypothesis: The development of AEs is associated with interferome and inflammasome pathway activation, leading to increased inflammatory cytokine and chemokine levels and enhanced immune activation. Additionally, pre-existing metabolic pathway perturbations may exacerbate AEs and serve as potential therapeutic targets. Aim 2: Identify mechanisms specific to reactogenicity versus protective immune response or those common to both. Hypothesis: Some mechanisms linked to severe AEs are also associated with stronger vaccine-induced immune responses. Aim 3: Model the impact of age and sex on mRNA COVID-19 vaccine-induced reactogenicity and immune response. Hypothesis: Older individuals, due to higher baseline inflammatory signatures, exhibit altered AE development and vaccine-specific immune responses following mRNA vaccination. Methodology: Veterans and, if necessary, some non-veterans will be enrolled to meet study targets. Participants will receive standard-of-care Pfizer or Moderna mRNA COVID-19 vaccines. Reactogenicity will be assessed clinically, and blood samples will be analyzed for cellular and transcriptomic changes, as well as vaccine-specific immune responses. Comprehensive systems biology analysis will compare individuals with high versus low AEs. Path to Translation/Implementation: Vaccine education interventions enhance trust in CDC recommendations and address concerns about rapid vaccine development and side eKects. Understanding the mechanisms driving reactogenicity will provide essential information to health care providers for patient education. Additionally, our findings may inform therapies or vaccine modifications to reduce AEs while preserving immune protection.", "keywords": [ "Ache", "Activities of Daily Living", "Address", "Adverse event", "Age", "Antigens", "Automobile Driving", "Bioinformatics", "Biological", "Biological Assay", "Blood specimen", "COVID-19", "COVID-19 mortality", "COVID-19 vaccination", "COVID-19 vaccine", "Cells", "Cellular Immunity", "Characteristics", "Chills", "Clinical", "Communities", "Data Set", "Development", "Disease", "Dose", "Educational Intervention", "Enrollment", "Event", "Exhibits", "FDA Emergency Use Authorization", "Fatigue", "Fright", "Headache", "Health", "Health Personnel", "Hour", "Immune", "Immune response", "Immunological Models", "Individual", "Inflammasome", "Inflammatory", "Inflammatory Response", "Influenza", "Injections", "Insecta", "Link", "Messenger RNA", "Metabolic", "Metabolic Pathway", "Methodology", "Modeling", "Moderna COVID-19 vaccine", "Modification", "Morbidity", "Muscle", "Mutate", "Older Population", "Outcome", "Pain", "Participant", "Pathway interactions", "Patient Education", "Patients", "Persons", "Phase", "Phase III Clinical Trials", "Population", "Predisposition", "Production", "Provider", "Publishing", "RNA vaccination", "RNA vaccine", "Reaction", "Recommendation", "Reporter", "Reporting", "Resources", "Respiratory Syncytial Virus Vaccines", "Role", "Serious Adverse Event", "Serology", "Serum", "Severities", "Side", "Site", "Systems Biology", "Technology", "Therapeutic", "Translations", "Trust", "United States National Institutes of Health", "Vaccination", "Vaccines", "Variant", "Veterans", "Work", "age effect", "chemokine", "cohort", "cytokine", "egg", "flu", "high dimensionality", "immune activation", "immunogenicity", "improved", "in vivo", "influenza virus vaccine", "innovation", "life span", "military veteran", "open label", "pathogen", "preservation", "prevent", "response", "sex", "standard of care", "therapeutic target", "therapy design", "transcriptomics", "uptake", "vaccination outcome", "vaccine acceptance", "vaccine development", "vaccine efficacy", "vaccine hesitancy", "vaccine immunogenicity", "vaccine platform", "vaccine reaction", "vaccine response", "vaccine side effects" ], "approved": true } }, { "type": "Grant", "id": "15948", "attributes": { "award_id": "1R21AI196828-01", "title": "N Protein Nexus: Rewiring Host Translation Machinery for SARS-CoV-2's Early Replicative Advantage", "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": 32891, "first_name": "MARY KATHERINE BRADFORD", "last_name": "PLIMACK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-01", "end_date": "2028-03-31", "award_amount": 213048, "principal_investigator": { "id": 23292, "first_name": "Rong", "last_name": "Hai", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1190, "ror": "", "name": "UNIVERSITY OF CALIFORNIA RIVERSIDE", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [ { "id": 44391, "first_name": "Sean E", "last_name": "O'Leary", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 3407, "ror": "", "name": "UNIVERSITY OF CALIFORNIA RIVERSIDE", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "ABSTRACT: Dependence on host-cell machinery for protein synthesis poses a significant challenge to coronavirus replication, particularly at the onset of infection when viral genomic RNA must compete with an abundance of host mRNAs for translation. To overcome this hurdle, viruses have evolved sophisticated strategies to commandeer the host translation machinery. While multiple mechanisms by which SARS-CoV-2 hijacks host translation have been elucidated, almost all involve non-structural viral proteins. This raises a fundamental question: how does SARS- CoV-2 establish a translational foothold during the early stages of infection, before non-structural proteins are synthesized? The viral nucleocapsid (N) protein is the primary viral factor present at this early stage of infection and has been shown to manipulate cell machinery to facilitate infection. We have found that N protein physically and functionally interacts with the human translation machinery, facilitating preferential viral translation. Moreover, our results suggest that the viral genome's 5ʹ untranslated region exploits high-affinity N protein binding to potentiate selective viral RNA recognition for translation. We hypothesize that N protein is a key mediator of viral translational hijacking in early SARS-CoV-2 infection, establishing a new paradigm within the N- protein functional repertoire. This proposal now seeks to elucidate the molecular mechanisms of host protein- synthesis modulation by N protein for viral benefit during early infection. Through two specific aims, we will (1) identify the viral determinants responsible for the impact of N protein on viral RNA translation and (2) delineate the roles of host factors in N protein viral-translation enhancement. By combining biochemical, biophysical, and genetic approaches, we will establish a comprehensive understanding of unanticipated host-virus interactions that govern SARS-CoV-2 pathogenesis, uncovering novel viral vulnerabilities that can be exploited to develop targeted antiviral therapy. Ultimately, this study will provide new insights for innovative therapeutic strategies that can be extended to other viruses with RNA-binding proteins, offering a promising avenue for smothering infection at its onset. 3", "keywords": [ "2019-nCoV", "Affinity", "Amino Acids", "Anti-viral Therapy", "Binding Proteins", "Biochemical", "Biology", "Biophysics", "COVID-19", "COVID-19 treatment", "Cells", "Communicable Diseases", "Coronavirus", "Dependence", "Elements", "Elongation Factor", "Face", "Genomic approach", "Human", "Infection", "Integration Host Factors", "Knowledge", "Life Cycle Stages", "Maps", "Mediating", "Mediator", "Messenger RNA", "Methods", "Molecular", "Nonstructural Protein", "Nucleocapsid", "Nucleocapsid Proteins", "Peptide Initiation Factors", "Phase", "Preparation", "Protein Biosynthesis", "Proteins", "RNA Viruses", "RNA-Binding Proteins", "RNA-Protein Interaction", "Recombinants", "Ribosomes", "Role", "SARS-CoV-2 genome", "SARS-CoV-2 infection", "SARS-CoV-2 pathogenesis", "Site", "Therapeutic", "Translations", "Untranslated RNA", "Untranslated Regions", "Viral", "Viral Genome", "Viral N Protein", "Viral Nonstructural Proteins", "Viral Proteins", "Virus", "antiviral drug development", "biophysical analysis", "biophysical techniques", "combat", "functional genomics", "genetic analysis", "genetic approach", "genomic RNA", "influenzavirus", "innovation", "insight", "mRNA Translation", "new therapeutic target", "novel", "pathogen", "pathogenic virus", "protein expression", "therapy development", "translational impact", "viral RNA", "viral genomics", "virus host interaction" ], "approved": true } }, { "type": "Grant", "id": "15945", "attributes": { "award_id": "1R21AI191344-01A1", "title": "Peptide-conjugated phosphodiamidate morpholino oligonucleotide (PPMO)-based henipavirus therapeutics", "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": 32808, "first_name": "MINDY I", "last_name": "DAVIS", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-01", "end_date": "2028-03-31", "award_amount": 475339, "principal_investigator": { "id": 8360, "first_name": "Christopher F", "last_name": "Basler", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 625, "ror": "https://ror.org/04a9tmd77", "name": "Icahn School of Medicine at Mount Sinai", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [ { "id": 44390, "first_name": "Hong M", "last_name": "Moulton", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 3404, "ror": "", "name": "ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus from the Henipavirus genus that causes severe respiratory disease and encephalitis in humans. To date, no antivirals have been approved for treatment or prevention of these infections. We will develop and test peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO)-based compounds as anti-NiV therapeutics. Phosphorodiamidate morpholino oligomers (PMO) are water soluble, nucleic-acid-like antisense agents having nuclease resistance. They form stable duplexes with complementary RNA, affecting function. PMOs are FDA-approved to treat forms of Duchenne muscular dystrophy. PMOs can be conjugated to a cell-penetrating peptide to produce peptide-PMO (PPMO) which enter cells without the need for transfection. Aqueous solutions of PPMOs have shown considerable antiviral efficacy against a number of RNA viruses. We evaluated the anti-henipavirus potential of PPMOs using the non-pathogenic henipavirus Cedar virus (CedV) at BSL2. We designed PPMOs to target the start codons for the mRNAs encoding the three viral proteins essential for viral RNA synthesis- nucleoprotein (N), phosphoprotein (P) and large protein (L). These exhibited low micromolar activity versus CedV replication in Vero cells. A pilot test of PPMO targeting NiV N and P demonstrated anti-NiV activity in cell culture. That the P gene is a viable target is notable because the NiV P gene also encodes two critical virulence factors, V and W, which disable the type I interferon response. Because V and W share the same N-terminus as the P protein, an inhibitor of P translation will also block V and W expression. Therefore, a single P-targeting PPMO could disable viral RNA synthesis and simultaneously promote antiviral IFN-I responses, potentially enhancing antiviral activity. Building on these data, we will design PPMOs to target NiV N, P and L mRNAs. These will be tested for inhibition against live NiV at BSL4 and mechanism of action assessed by using a BSL2 NiV minigenome assay. We will test the hypotheses that antiviral activity of PPMOs correlates with suppression of translation of the targeted mRNA and determine whether targeting the P start codon will augment PPMO antiviral effects by suppressing expression of V and W. We will then test the best performing PPMO in vivo, using a hamster model. We will use airway administration because (1) Respiratory symptoms are a significant component of NiV infection. (2) In hamsters, infection can spread from the airway to the central nervous system (CNS) via the olfactory bulb. (3) Prior studies have used respiratory delivery and respiratory NiV challenge to test therapeutic candidates. (4) We recently demonstrated that PPMOs delivered directly to the airway at a 1 mg/kg dose reduced SARS-CoV-2 lung titers by >104 infectious units per gram lung tissue, and our Preliminary Data demonstrates that intranasal delivery to mice results in sustained PPMO effects throughout the upper airway and extending into the olfactory bulb. The in vivo studies will include assessment of tolerability, tissue distribution and efficacy against NiV of the top performing PPMO. 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