Grant List
Represents Grant table in the DB
GET /v1/grants?sort=-principal_investigator
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-principal_investigator", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1424&sort=-principal_investigator", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=2&sort=-principal_investigator", "prev": null }, "data": [ { "type": "Grant", "id": "15995", "attributes": { "award_id": "1IK2HX003695-01A2", "title": "Improving Specialty Care Through Virtual Care Models", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2026-01-01", "end_date": "2030-12-31", "award_amount": null, "principal_investigator": { "id": 44448, "first_name": "Rebecca", "last_name": "Tisdale", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3442, "ror": "", "name": "VETERANS ADMIN PALO ALTO HEALTH CARE SYS", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "1 Background: Specialty care deserts—the absence of specialists in geographic regions—have led to an access 2 crisis for the VA. In addition to increasing wait times and causing delays in care, these access needs drive many 3 Veterans to seek care outside VA, resulting in fragmented care, increased risks for hospitalization and hospital 4 readmission, and higher costs. In response, VA has launched the Clinical Resource Hub (CRH) program, which 5 seeks to deliver virtual care from “hub” to “spoke” sites in VA. VISN 21 has begun implementing this model in 6 cardiology at several spoke sites, but little is known about how care utilization and quality within the program. 7 Significance/Impact: This work seeks to better understand the effects of a virtual model of specialty care, in 8 this case cardiology care, on Veterans’ care access and quality. In addition, it aligns closely with several VA and 9 HSR&D priorities, chiefly access to care, virtual care/telehealth, and advancing the goals of the MISSION Act. 10 Innovation: The CRH program and the virtual care model at its core have yet to be studied in depth, and there 11 is no research in progress regarding specialty CRH despite strong interest at the national VA level in 12 understanding how specialty CRH is used and associated outcomes. Given that virtual cardiology care was very 13 limited prior to the COVID-19 pandemic, cardiology CRH is particularly novel. Hence, this project would add to 14 the limited body of research examining virtual cardiology care in the VA. In addition, the proposed work seeks to 15 evaluate this virtual care model at a time of unprecedented choice for Veterans between in-person and virtual 16 care, and limited data on how best to integrate these modalities. 17 Specific Aims: The proposed CDA will offer mentorship and training for me to pursue the following aims: 18 Aim 1. Evaluate quality of cardiology care associated with CRH implementation with administrative data. 19 I will use adjusted difference-in-difference event studies to compare cardiology quality metric achievement for 20 patients who received cardiology care via CRH versus those who received conventional VA-based cardiology care. 21 Aim 2. Assess Veteran perceptions of quality of cardiology care delivered via CRH. 22 I will interview Veterans participating in the CRH program and their caregivers regarding their experiences and 23 perceptions of quality of CRH cardiology care and elicit suggestions for key metrics to focus on for improvement. 24 Aim 3. Construct intervention to track and improve access to high-quality, equitable care through CRH. 25 Building on finding from Aims 1 and 2, I will interview clinicians and employ a facilitated deliberative process with 26 an expert advisory group to construct and pilot an intervention to improve quality. 27 Methodology: In Aim 1, I will use a difference-in-difference event study design to assess the impact of the program 28 on a battery of validated and/or guideline-based quality of cardiology care metrics. In Aim 2, guided by the Fortney 29 model of care access and quality, I will conduct semi-structured interviews of Veterans and caregivers receiving 30 care through the VISN 21 CRH program to understand their experiences with the CRH program and what outcomes 31 they recommend to include in a quality improvement intervention. In Aim 3, I will interview clinicians (Aim 3.1) and 32 conduct a facilitated deliberation process (Aim 3.2) to inform the construction of an intervention (proactive panel 33 management using a clinical dashboard tool) to track and improve quality of care and pilot the intervention. 34 Next Steps/Implementation: To continue moving this research into practice to improve health outcomes for 35 Veterans, I will extend the analysis of cardiology quality of care to compare cardiology care in the community to 36 CRH care. In addition, I will assess the effect of the intervention constructed in Aim 3 on patient outcomes and 37 clinician satisfaction via a hybrid implementation-effectiveness trial. I will continue to work with operational partners 38 to ensure cardiology CRH is improving access to high-quality cardiology care for Veterans. This project supports 39 my goal of becoming an independent VA health services researcher and leader in optimizing cardiovascular 40 disease care access, value, and equity for Veterans through virtual care innovations and implementation.", "keywords": [ "Achievement", "Address", "Area", "COVID-19 pandemic", "California", "Cardiology", "Cardiovascular Diseases", "Cardiovascular system", "Caregivers", "Caring", "Characteristics", "Cladribine", "Clinical", "Clinical Services", "Communities", "Community Health Care", "Dangerousness", "Data", "Disease", "Ensure", "Equity", "Evaluation", "Event", "Geographic Locations", "Goals", "Guidelines", "Health", "Health Services", "Health Services Accessibility", "Heart failure", "Homogeneously Staining Region", "Hospitalization", "Hospitals", "Improve Access", "Intervention", "Interview", "Medical", "Mentors", "Mentorship", "Methodology", "Methods", "Modality", "Modeling", "Morbidity - disease rate", "Nevada", "Outcome", "Pacific Islands", "Patient-Focused Outcomes", "Patients", "Perception", "Persons", "Physicians", "Policies", "Positioning Attribute", "Process", "Qualitative Methods", "Quality of Care", "Recommendation", "Research", "Research Design", "Research Personnel", "Resources", "Risk", "Rural Health", "Safety", "Site", "Specialist", "Structure", "Suggestion", "Telemedicine", "Telephone", "Testing", "Time", "Training", "Training Activity", "Veterans", "Visit", "Wait Time", "Work", "adverse outcome", "care fragmentation", "care seeking", "care utilization", "clinical implementation", "connected care", "cost", "dashboard", "design", "effectiveness/implementation trial", "experience", "follow-up", "health economics", "hospital readmission", "hospitalization rates", "implementation efforts", "implementation science", "improved", "innovation", "insight", "interest", "intervention effect", "medical specialties", "mortality", "novel", "operation", "patient subsets", "pilot test", "preference", "programs", "rapid growth", "research to practice", "response", "rural counties", "satisfaction", "sociodemographics", "southern nevada", "telehealth", "therapy design", "tool", "virtual", "virtual delivery", "virtual health care", "virtual model" ], "approved": true } }, { "type": "Grant", "id": "15994", "attributes": { "award_id": "1F31AI181508-01A1", "title": "Investigating the Role of Epstein-Barr Virus in Long COVID Pathogenesis", "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": 32795, "first_name": "EUN-CHUNG", "last_name": "PARK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-01-16", "end_date": "2028-01-15", "award_amount": 33538, "principal_investigator": { "id": 44447, "first_name": "Alexandra", "last_name": "Tabachnikova", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3441, "ror": "", "name": "YALE UNIVERSITY", "address": "", "city": "", "state": "CT", "zip": "", "country": "United States", "approved": true }, "abstract": "SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease, which is known as Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Previously, this research group profiled 177 individuals in an exploratory, cross-sectional study encompassing multi-dimensional immune phenotyping in conjunction with machine learning. Key immunological features distinguishing Long COVID were identified and described in the Mount Sinai Yale –Long COVID (MY-LC) study. A striking finding was an elevation in antibodies to lytic antigens of Epstein-Barr Virus (EBV) in Long COVID participants, which may be indicative of more recent reactivation of EBV in these patients. In addition, levels of these antibodies correlated with IL-4, IL-6 cytokine double-producing CD4+ T- cells, which suggests that EBV reactivation is not merely incidental but reflects, mediates or aggravates immune perturbations in these patients. The overarching goal of this proposal is to provide a thorough insight into whether EBV reactivation contributes to LC disease pathogenesis and symptomatology, building on current literature. The research plan proposed will utilize the Iwasaki lab’s expertise in in vitro and in vivo modeling to assess whether SARS-CoV-2 infection can reactivate EBV and contribute to lasting sequelae, as described in Aim 1. Aim 2 will leverage large patient cohorts previously recruited through the MY-LC study and robust sample and data availability to test whether patients with Long COVID characterized by recent EBV reactivation experience unique immune alterations. Aim 2 will also test whether these responses correlate to unique symptoms. The findings uncovered by these studies have the potential to deepen understanding of one cause of Long COVID, and to inform future treatment of a growing, currently largely-untreated patient population. Mentorship from an interdisciplinary group of collaborators, who are experts in the proposed techniques, will facilitate this applicant’s training as an independent immunologist.", "keywords": [ "2019-nCoV", "Acute", "Acute Disease", "Antibodies", "Antigens", "Autoimmunity", "Autonomic Dysfunction", "B-Lymphocytes", "Biological", "Biological Assay", "Blood specimen", "CD4 Positive T Lymphocytes", "COVID-19", "COVID-19 impact", "COVID-19 pathogenesis", "COVID-19 patient", "Cell Culture Techniques", "Cells", "Communication", "Computational Technique", "Cross-Sectional Studies", "DNA Viruses", "Data", "Development", "Diagnosis", "Dimensions", "Disease", "Disease Marker", "EBV reactivation from latency", "Elements", "Epstein-Barr Virus latency", "Exertion", "Exhibits", "Fatigue", "Functional disorder", "Future", "Glycoproteins", "Goals", "Herpesviridae", "Hospitalization", "Human", "Human Herpesvirus 4", "Immune", "Immune response", "Immunologics", "Immunologist", "Impaired cognition", "Impairment", "In Vitro", "Individual", "Infection", "Inflammatory", "Influenza", "Influenza A Virus H1N1 Subtype", "Interleukin-4", "Interleukin-6", "Laboratories", "Literature", "Long COVID", "Lymphopenia", "Lytic", "Lytic Virus", "Machine Learning", "Malaise", "Mediating", "Memory", "Mentorship", "Methods", "Multiple Sclerosis", "Muridae", "Mus", "Neurocognitive", "Participant", "Pathogenesis", "Pathology", "Patients", "Phenotype", "Plasma", "Production", "Quality of life", "Recovery", "Reporting", "Research", "Rheumatoid Arthritis", "Risk", "Role", "SARS-CoV-2 infection", "Sampling", "Serology", "Serum", "Severity of illness", "Study Subject", "Symptoms", "Systemic Lupus Erythematosus", "T cell response", "T-Lymphocyte", "Techniques", "Testing", "Training", "Viral Antigens", "Viremia", "Virus Diseases", "Virus Latency", "Writing", "acute COVID-19", "autoimmune pathogenesis", "brain fog", "chronic infection", "cohort", "comparison control", "cytokine", "daily functioning", "debilitating symptom", "experience", "experimental study", "in vivo", "in vivo Model", "insight", "mortality", "mouse model", "patient population", "persistent symptom", "recruit", "response", "skills", "symptomatology", "virus envelope" ], "approved": true } }, { "type": "Grant", "id": "15993", "attributes": { "award_id": "1F30AI194459-01", "title": "Testing the role of microbial infections in the development of auto-antibodies to type I interferons", "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": 32556, "first_name": "TIMOTHY A", "last_name": "GONDRE-LEWIS", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-01-27", "end_date": "2029-01-26", "award_amount": 43914, "principal_investigator": { "id": 44446, "first_name": "Adrianna M.", "last_name": "Rivera-León", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3440, "ror": "", "name": "UNIVERSITY OF MINNESOTA", "address": "", "city": "", "state": "MN", "zip": "", "country": "United States", "approved": true }, "abstract": "Type I interferons (IFN) are crucial to anti-viral immunity. Neutralizing autoantibodies (AAb) to IFN are found in the general population, increase in prevalence with age, and are linked to worse, often fatal, outcomes in some of the most lethal acute respiratory viral diseases known to date, including fulminant influenza and COVID-19 pneumonia. Despite this, the mechanisms behind the formation of IFN AAb remain unknown. Human data suggest that impairments in thymic tolerance—due to dysfunction of autoimmune regulator (AIRE) and medullary thymic epithelial cells (mTEC)—may be required for the development of IFN AAb. AIRE is a transcription factor expressed by mTEC that is essential for establishing T cell tolerance in the thymus. In mTEC, AIRE promotes the expression and presentation of antigens from extrathymic tissues to developing T cells (thymocytes). This allows for the elimination of auto-reactive thymocyte clones, thereby preventing autoimmunity. Interestingly, AIRE+ mTEC have been shown to express IFN at steady-state conditions in the thymus suggesting that, in this context, AIRE+ mTEC act as antigen-presenting cells to thymocytes to mediate T cell tolerance to IFN. Supporting this idea, individuals with Autoimmune Polyglandular Syndrome 1 (APS1), who lack AIRE and experience T cell tolerance loss, consistently develop IFN AAb. These AAb are isotype- switched and somatically hypermutated, supporting the notion that a failure of T cell tolerance, rather than solely B cell tolerance, is necessary for their generation. However, additional findings suggest that loss of thymic T cell tolerance alone is insufficient for IFN AAb to develop. First, APS1 patients do not typically present IFN AAb at birth or infancy; instead, they develop these AAb later in life after exposure to pathogens is likely to have occurred. Second, IFN AAb have not been observed in specific pathogen-free, Aire-deficient mice. Combined, these observations suggest that pathogen exposure, in addition to AIRE and mTEC dysfunction, may be required for IFN AAb to develop. This proposal aims to understand how infections, combined with AIRE deficiency, contribute to the loss of thymic tolerance to IFN. My central hypothesis is that in individuals with predisposing AIRE deficiency, infections that induce IFN expression act as a double hit, promoting the development of neutralizing IFN AAb. Until now, methods to detect neutralizing IFN AAb in mice have been lacking, which has hindered the field's ability to test this hypothesis. I have developed a novel, sensitive, reproducible, and high-throughput assay for detecting murine neutralizing IFN AAb. This new tool will serve as the basis for this proposal and will facilitate exploration of how microbial infections and thymic defects contribute to the development of IFN AAb in an animal model. The findings from this work will deepen our understanding of how tolerance to IFN is mediated and may inform strategies to prevent IFN AAb development in affected individuals.", "keywords": [ "Academia", "Acute", "Affect", "Affinity", "Age", "Animal Model", "Antibody Affinity", "Antigen Presentation", "Antigen-Presenting Cells", "Antigens", "Autoantibodies", "Autoimmune Polyendocrinopathies", "Autoimmune Regulator", "Autoimmunity", "B-Lymphocytes", "Binding", "Biological Assay", "Birth", "CD4 Positive T Lymphocytes", "COVID-19 pandemic", "COVID-19 pneumonia", "Cells", "Cerebrum", "Chronic", "Clinical", "Clonal Deletion", "Clone Cells", "Competence", "Data", "Defect", "Development", "Epitopes", "Event", "Exposure to", "Failure", "Flow Cytometry", "Frequencies", "Functional disorder", "General Population", "Generations", "Human", "Immune system", "Immunoglobulin Class Switching", "Immunologics", "Impairment", "Individual", "Infection", "Interferon Type I", "Interferons", "Knockout Mice", "Life", "Life Experience", "Link", "Luciferases", "Lymphocytic choriomeningitis virus", "Measures", "Mediating", "Methods", "Microbe", "Modeling", "Mus", "Mutation", "Organ", "Outcome", "Patients", "Peptides", "Play", "Prevalence", "Process", "Regulatory T-Lymphocyte", "Reporting", "Reproducibility", "Research", "Risk Factors", "Role", "Severity of illness", "T-Lymphocyte", "Testing", "Thymic Tissue", "Thymic epithelial cell", "Thymus Gland", "Tissues", "Training", "Virus Diseases", "Wild Type Mouse", "Work", "age related", "aged", "aging population", "antiviral immunity", "autoreactive T cell", "autoreactivity", "career", "comparative", "cytokine", "detection assay", "experience", "experimental study", "germ free condition", "high throughput screening", "human data", "infancy", "influenza pneumonia", "interest", "later life", "loss of function mutation", "microbial", "novel", "pathogen", "pathogen exposure", "peptide vaccination", "prevent", "public health relevance", "respiratory", "response", "severe COVID-19", "thymocyte", "tool", "transcription factor" ], "approved": true } }, { "type": "Grant", "id": "15991", "attributes": { "award_id": "1R01NR021708-01A1", "title": "What interventions to reduce hospital nurse burnout are most effective?", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Nursing Research (NINR)" ], "program_reference_codes": [], "program_officials": [ { "id": 44444, "first_name": "KAREN MARIE", "last_name": "MCNAMARA", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-01-30", "end_date": "2029-12-31", "award_amount": 1422387, "principal_investigator": { "id": 44445, "first_name": "EILEEN T", "last_name": "LAKE", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2627, "ror": "", "name": "UNIVERSITY OF PENNSYLVANIA", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "What Interventions to Reduce Hospital Nurse Burnout Are Most Effective? Nurse burnout is a threat to healthcare safety, and to nurse and patient outcomes. Burnout among nurses has been a long-standing concern only accelerated by the COVID-19 pandemic. Burnout is a syndrome caused by chronic workplace stress and characterized by feelings of emotional exhaustion, cynicism towards one’s work, and decreased professional efficacy. Pre-pandemic, about 30% of nurses were burned out. Today, nearly half of 4.7 million nurses are experiencing burnout. This unsustainable high level of burnout has dire consequences for nurses and patients alike. Nurse burnout is associated with higher odds of patient mortality, failure to rescue, and prolonged length of stay, as well as nurse job dissatisfaction and turnover. We propose to integrate two approaches to addressing burnout: investigation of organizational characteristics as determinants of burnout, notably conducted by the proposed research team in recent decades, and health system administrators’ current implementation of interventions to reduce nurse burnout. Our preliminary studies reveal that organizational and individual interventions are being implemented nationwide and that nurses prefer organizational ones. It is unknown how preferred and implemented interventions relate to hospitals’ performance on nurse burnout, individual nurse burnout, and reducing burnout over time. Crucially, whether these interventions’ effectiveness depends on the work environment is unknown. Integration of these two approaches will yield a representation of reality across a large, geographically diverse hospital sample to inform whether certain intervention combinations are most effective and in what organizational contexts. The proposed aims address the Notice of Special Interest NOT-NR-23-012, “Addressing Organizational Factors to Prevent or Mitigate Nurse Burnout,” which invites “research studies to develop and evaluate novel organizational interventions to prevent and mitigate nurse burnout,” by identifying the currently preferred and implemented interventions, their work environment contexts, and their relation to nurse burnout, dissatisfaction, and intent to leave and hospital performance on nurse burnout. We propose to conduct a cross-sectional and longitudinal observational study utilizing 2024 and 2026 hospital nurse survey data from 31,942 nurses in 1,278 hospitals (in 2024) in 10 U.S. states to determine how preferred and implemented interventions relate to hospitals’ performance on nurse burnout, individual nurse burnout, and reducing burnout over time. The potential impact of the proposed study would be high because it would provide actionable results to optimize burnout intervention choices and contexts to mitigate pervasive nurse burnout.", "keywords": [ "Acceleration", "Address", "Administrator", "Burn injury", "COVID-19 pandemic", "Characteristics", "Chronic", "Data", "Effectiveness of Interventions", "Emotional", "Failure", "Feeling", "Geography", "Health Care", "Health Resources", "Health system", "Hospital Nursing", "Hospitals", "Individual", "Intervention", "Investigation", "Length of Stay", "Longitudinal observational study", "Mental Health", "Nurses", "Occupations", "Patient-Focused Outcomes", "Patients", "Research", "Respondent", "Safety", "Sampling", "Stress", "Surveys", "Syndrome", "Time", "Work", "Workplace", "burnout", "exhaustion", "experience", "hospital performance", "implementation intervention", "improved", "interest", "mortality", "novel", "pre-pandemic", "prevent", "professional atmosphere", "research study", "success" ], "approved": true } }, { "type": "Grant", "id": "15987", "attributes": { "award_id": "1R21AI196149-01", "title": "Identification of Novel Targets for Enhancing Targeted RNA Degradation in Antiviral Discovery", "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": 32536, "first_name": "DIPANWITA", "last_name": "BASU", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-02-05", "end_date": "2028-01-31", "award_amount": 451000, "principal_investigator": { "id": 44441, "first_name": "Jingxin", "last_name": "Wang", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3437, "ror": "", "name": "UNIVERSITY OF CHICAGO", "address": "", "city": "", "state": "IL", "zip": "", "country": "United States", "approved": true }, "abstract": "/ ABSTRACT The development of targeted RNA degradation (TRD) technologies, such as RNA-degrading chimeras, holds significant promise for antiviral therapies by reducing viral RNA levels to prevent viral replication. Despite their potential, current TRD mechanisms exhibit limited potency. In various literature reports, ribonuclease- targeting chimeras (RIBOTACs) exemplify this problem, achieving only ~75% maximum degradation of distinct RNA targets in cells. For example, our preliminary work optimized a synthetic RNA ligand, C34, which binds robustly to an RNA G bulge in the 5’ untranslated region of SARS-CoV-2’s RNA genome with a low nanomolar dissociation constant. However, the minimum inhibitory concentration (MIC) of the C34-based RIBOTAC remained moderately high at 20 μM in SARS-CoV-2-infected cells, indicating insufficient cellular potency. RIBOTAC is a drug-induced TRD modality utilizing an endogenous ribonuclease, RNase L. Interestingly, this RIBOTAC potency cap in cells was not observed in cell-free assays using purified recombinant RNase L, indicating the possible presence of cellular factors that inhibit the RNase L degradation complex. To address this potency limitation, the proposed project aims to discover novel cellular targets to significantly enhance RNase L activity and brand-new TRD mechanisms for future drug development through two specific aims. Aim 1 focuses on identifying cellular determinants that inhibit RNase L-dependent RIBOTAC activity using a genome-wide CRISPR knockout screen. By targeting these inhibitory genes, we aim to significantly boost the efficacy of existing RIBOTACs. Aim 2 focuses on discovering novel cellular targets for TRD by performing genome-wide screenings in three screening platforms. We will utilize a plasmid library comprising ~14,000 open reading frames from the human genome to identify candidate genes that can effectively induce TRD through drug-induced proximity. Both aims will leverage a SARS-CoV-2 cellular model and our optimized RNA ligand C34 to validate these new mechanisms in antiviral research. Ultimately, this project seeks to expand our chemical genetics toolbox by unveiling new mechanisms and targets for RNA degradation. These advancements will be pivotal in developing new chimeric molecules designed to combat a variety of infectious diseases, significantly enhancing our capacity to address global health challenges. 1", "keywords": [ "2019-nCoV", "5' Untranslated Regions", "Address", "Anti-viral Therapy", "Autophagocytosis", "Bar Codes", "Binding", "Biochemical", "Biological Assay", "Candidate Disease Gene", "Cell model", "Cells", "Chimera organism", "Clinical", "Clustered Regularly Interspaced Short Palindromic Repeats", "Communicable Diseases", "Complex", "DNA", "Data", "Degradation Pathway", "Development", "Dissociation", "Exhibits", "Exposure to", "Flow Cytometry", "Future", "Gene Targeting", "Genes", "Genome", "Guide RNA", "Human", "Human Genome", "Individual", "Infection", "Infection Control", "Integration Host Factors", "Knock-out", "Libraries", "Life Cycle Stages", "Ligands", "Literature", "Luciferases", "Minimum Inhibitory Concentration measurement", "Minor Groove", "Modality", "Modeling", "Open Reading Frames", "Pancreatic ribonuclease", "Pathway interactions", "Pharmaceutical Preparations", "Plasmids", "Protac", "Proteins", "Protocols documentation", "RNA", "RNA Binding", "RNA Degradation", "Recombinants", "Reporting", "Research", "Ribonucleases", "Structure", "Tacrolimus Binding Proteins", "Technology", "Therapeutic", "Untranslated RNA", "Untranslated Regions", "Viral", "Virus", "Virus Replication", "Work", "antiviral drug development", "arm", "candidate identification", "candidate validation", "cellular targeting", "chemical genetics", "combat", "cytotoxicity", "design", "drug development", "drug discovery", "druggable target", "genome wide screen", "genome-wide", "global health", "human disease", "improved", "inhibitor", "interest", "nanomolar", "novel", "novel therapeutics", "pharmacologic", "prevent", "protein degradation", "recruit", "screening", "success", "transcriptome sequencing", "viral RNA", "virulence gene", "whole genome" ], "approved": true } }, { "type": "Grant", "id": "15985", "attributes": { "award_id": "1R21AI197441-01", "title": "Sphingolipids and Innate Immunity", "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": 44439, "first_name": "RAJEEV", "last_name": "GAUTAM", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-02-06", "end_date": "2028-01-31", "award_amount": 195000, "principal_investigator": { "id": 44440, "first_name": "Fikadu G.", "last_name": "Tafesse", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3435, "ror": "", "name": "OREGON HEALTH & SCIENCE UNIVERSITY", "address": "", "city": "", "state": "OR", "zip": "", "country": "United States", "approved": true }, "abstract": "Type I interferon (IFN) is the first line of defense in innate antiviral immunity, orchestrating transcriptional and metabolic responses that restrict viral replication. While IFN signaling is known to modulate sterol and glycerolipid pathways, its impact on sphingolipids (SPLs)—a class of bioactive lipids involved in immune signaling and cell stress responses—remains poorly understood. Mounting evidence suggests that infections by RNA viruses, including flaviviruses and coronaviruses, induce the accumulation of ceramide (Cer), but whether this promotes viral replication or enhances antiviral defenses is unclear. Our preliminary studies show that Zika virus (ZIKV) triggers overall changes in SPL composition and relies on Cer biosynthesis for successful infection. However, other studies implicate Cer in restricting viral replication and promoting cell survival, raising the possibility that these lipids are upregulated by the host response rather than the virus. The central goal of this proposal is to uncover how type I IFN affects SPL metabolism and to determine whether these lipids, in turn, control the IFN response and infection outcomes. We hypothesize that SPLs, particularly Cer, play a dual role in infection and immunity. Viruses may induce Cer to suppress innate immune responses, including IFN production, as suggested by the known roles of Cer in modulating host signaling pathways. However, we also propose that IFN itself alters SPL metabolism, as it does with other lipid classes, and that these IFN-induced lipid changes may contribute to antiviral defense. To disentangle these possibilities, we will use a combination of untargeted lipidomics, innovative SPL probes, CRISPR gene editing, and organelle-targeted lipid perturbation to systematically determine the causes and consequences of SPL dysregulation in infection. Aim 1 will define how IFN-β alters SPL content and distribution in infected and uninfected cells. In doing so, we will generate the first comprehensive map of IFN-driven changes in the cellular lipidome—including SPLs—across multiple cell types, providing a foundational resource for the broader virology and immunometabolism communities. Aim 2 will determine whether Cer regulates IFN-β signaling and antiviral defense, and whether the subcellular location of Cer influences its role as a pro- or anti-viral signal. Together, these studies will determine how IFN shapes and is shaped by SPLs, providing fundamental insight into the role of these lipids in the earliest steps of antiviral innate immunity.", "keywords": [ "Acceleration", "Affect", "Anabolism", "Anti-viral Agents", "Anti-viral Response", "Autoimmune Diseases", "Cell Survival", "Cell model", "Cells", "Cellular Stress", "Ceramides", "Clustered Regularly Interspaced Short Palindromic Repeats", "Communities", "Coronavirus", "Data", "Disease", "Double-Stranded RNA", "Drug Targeting", "Enzymes", "Family", "Flavivirus", "Genes", "Genetic", "Genetic Transcription", "Goals", "Host Defense", "Host Defense Mechanism", "Immune response", "Immune signaling", "Immunity", "Infection", "Innate Immune Response", "Interferon Type I", "Interferon-β", "Interferons", "Knock-out", "Lipids", "Location", "Malignant Neoplasms", "Maps", "Membrane", "Metabolic", "Metabolic Pathway", "Metabolism", "Natural Immunity", "Organelles", "Outcome", "Pathway interactions", "Play", "Process", "Production", "RNA Virus Infections", "RNA Viruses", "Resources", "Risk", "Role", "Shapes", "Signal Pathway", "Signal Transduction", "Sphingolipids", "Sterols", "Time", "Viral", "Viral Pathogenesis", "Viral Physiology", "Virus", "Virus Diseases", "Virus Replication", "Visual", "Work", "ZIKV infection", "Zika Virus", "antiviral immunity", "biological adaptation to stress", "cell type", "cytokine", "drug repurposing", "global health", "innovation", "insight", "lipid biosynthesis", "lipid metabolism", "lipidome", "lipidomics", "mosquito-borne pathogen", "novel", "pandemic potential", "pharmacologic", "programs", "response", "therapeutic target", "tool", "virology" ], "approved": true } }, { "type": "Grant", "id": "15983", "attributes": { "award_id": "1R35GM162443-01", "title": "Molecular Mechanisms of Antimicrobial Resistance from Machine Learning Augmented Enhanced Sampling", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 44257, "first_name": "ANNE", "last_name": "GERSHENSON", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-02-24", "end_date": "2030-12-31", "award_amount": 401285, "principal_investigator": { "id": 44438, "first_name": "Dhiman", "last_name": "Ray", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3433, "ror": "", "name": "UNIVERSITY OF OREGON", "address": "", "city": "", "state": "OR", "zip": "", "country": "United States", "approved": true }, "abstract": "ABSTRACT: Antimicrobial resistance threatens our ability to treat previously curable infectious diseases and may soon become a global public health crisis. The Ray group aims to understand and characterize the molecular mechanisms of antibiotic and antiviral resistance to identify potential avenues to target resistant pathogens. This R35 MIRA pro- gram involves two distinct research projects that utilize advanced machine learning (ML) and enhanced sampling algorithms for molecular dynamics (MD) simulations to gain mechanistic insights into antimicrobial resistance and facilitate the development of future therapeutic applications. In the first project, we will study the process of ligand binding to riboswitches, a class of regulatory RNA segments that are potential targets for next-generation antibi- otics. Our goal is to identify the role of conformational dynamics and distant nucleotide mutations in modulating the binding mechanism of the small molecule inhibitors (e.g., Ribocil) to RNA targets (e.g., Flavin-mononucleotide (FMN) riboswitch). We will design neural network (NN) and explainable artificial intelligence (XAI) based collec- tive variables from system agnostic descriptor space and perform enhanced sampling simulations to compute the free energy landscape of riboswitch conformational transition and ligand binding. This work will provide key mechanistic insights into RNA-small-molecule interactions and pave the way for designing more resilient antibi- otics. In the second project, we will study how resistant mutations in the viral antigens, e.g., SARS-CoV-2 spike protein, affect the binding mechanism of neutralizing antibodies. Previous research in this area primarily focused on the antigen-antibody interface but often overlooked the long-range allosteric effect of antigen mutations on the antibody binding process. We will perform NN and XAI-guided enhanced sampling simulations to elucidate the mechanistic details of antigen-antibody recognition. In addition, we will trace the allosteric communication path- ways using mutual-information-based protein graph connectivity networks constructed for various intermediate configurations sampled from the association pathway. This work will open new avenues for the rational design of broad-spectrum monoclonal antibodies through the judicious strengthening of distant regions of the antibody structure that are less susceptible to epitope mutations.", "keywords": [ "Affect", "Algorithms", "Antibiotics", "Antibodies", "Antigens", "Antimicrobial Resistance", "Area", "Bacterial RNA", "Binding", "Communicable Diseases", "Communication", "Computer Simulation", "Descriptor", "Development", "Distant", "Epitopes", "Flavin Mononucleotide", "Free Energy", "Future", "Goals", "Graph", "Ligand Binding", "Machine Learning", "Molecular", "Molecular Conformation", "Monoclonal Antibodies", "Mutation", "Nucleotides", "Pathway interactions", "Pharmaceutical Preparations", "Predisposition", "Process", "Proteins", "Public Health", "RNA", "Research", "Research Project Grants", "Resistance", "Resistance development", "Role", "SARS-CoV-2 spike protein", "Sampling", "Small RNA", "Structure", "System", "Therapeutic", "Viral Antigens", "Viral Drug Resistance", "Viral Proteins", "Work", "conformational conversion", "design", "drug candidate", "explainable artificial intelligence", "future antibiotics", "insight", "molecular dynamics", "neural network", "neutralizing antibody", "novel therapeutic intervention", "pathogen", "programs", "rational design", "resilience", "resistance mutation", "simulation", "small molecule", "small molecule inhibitor" ], "approved": true } }, { "type": "Grant", "id": "15982", "attributes": { "award_id": "1R01AI189532-01A1", "title": "Biophysical constraints on antibody affinity maturation to SARS-CoV-2", "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": "2026-02-19", "end_date": "2031-01-31", "award_amount": 815762, "principal_investigator": { "id": 44437, "first_name": "Angela Marie", "last_name": "Phillips", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2635, "ror": "", "name": "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "The objective of this proposal is to develop a quantitative understanding of how the biophysical properties of antibodies impact their capacity to evolve affinity to divergent SARS-CoV-2 spike variants. Though there is substantial evidence that mutations acquired during affinity maturation impact antibody expression, affinity for distinct viral variants, and self-reactivity, we lack a quantitative understanding of (1) how mutations impact these biophysical properties and (2) how these properties, and trade-offs between them, collectively determine the fate of the corresponding B-cell lineage. Here, we propose three Aims to test our hypothesis that mutations differentially impact antibody expression, affinity, and self-reactivity, resulting in biophysical trade-offs that constrain the evolution of antibodies that bind divergent SARS-CoV-2 spike variants. In Aim 1, we quantitate the biophysical effects of mutations in anti-SARS-CoV-2 spike antibodies, using high-throughput mammalian cell- display methods we recently developed. By measuring the expression, affinity, and self-reactivity for millions of anti-spike antibodies, including broadly neutralizing antibodies (bnAbs) that bind divergent spike variants, their evolutionary predecessors, and systematically mutagenized antibody sequences, we will unveil biophysical constraints that shape affinity maturation to rapidly evolving viral antigens. In Aim 2, we evaluate the contributions of antibody biophysical properties to B-cell fitness, or proliferation, using longitudinally-sampled patient B-cells following exposure to divergent strains of SARS-CoV-2. This approach will reveal the relative importance of distinct antibody biophysical properties in driving B-cell evolutionary dynamics in human repertoires and enable development of quantitative models for predicting the outcomes of affinity maturation. In Aim 3, we define the impact of selection pressure during affinity maturation on the biophysical properties of the resulting antibodies, focusing on selection regimes known to favor the maturation of bnAbs that bind distinct spike variants. To this end, we leverage a B-cell directed evolution platform that mimics the mutagenic load of somatic hypermutation, enables fine-tuning of the antibody selection conditions, and supports longitudinal B-cell sampling to profile the evolutionary dynamics of the B-cell response and the biophysical properties of the corresponding antibody lineages. The resulting data will be used to define the impact of the selection regime on the biophysical determinants of B-cell fitness. Successful completion of these Aims will yield quantitative insight into (1) how antibody biophysical properties change during affinity maturation, (2) how they collectively determine B-cell fate in human repertoires, and (3) how their relative importance varies across distinct selection regimes. Thus, this work will advance our fundamental understanding of the biophysical mechanisms that shape antibody affinity maturation to rapidly evolving pathogens like SARS-CoV-2, supporting efforts to design and elicit antibodies that bind existing and novel viral variants.", "keywords": [ "2019-nCoV", "Affinity", "Antibodies", "Antibody Affinity", "Antibody Repertoire", "Antigens", "Autoantibodies", "Automobile Driving", "B-Cell Antigen Receptor", "B-Lymphocytes", "Binding", "Biophysical Process", "Biophysics", "Cell Lineage", "Cell membrane", "Cell surface", "Data", "Development", "Directed Molecular Evolution", "Engineering", "Epitopes", "Evolution", "Exposure to", "Frequencies", "Future", "Goals", "Human", "Immunoglobulin Somatic Hypermutation", "Knowledge", "Mammalian Cell", "Measures", "Membrane", "Methods", "Modeling", "Molecular", "Mutagens", "Mutation", "Outcome", "Patients", "Population", "Process", "Proliferating", "Property", "Protein Engineering", "Proteins", "Regimen", "Relaxation", "Research", "SARS-CoV-2 antibody", "SARS-CoV-2 exposure", "SARS-CoV-2 spike protein", "SARS-CoV-2 variant", "Sampling", "Shapes", "Surface", "Testing", "Vaccines", "Variant", "Viral", "Viral Antigens", "Virus", "Work", "adaptive immunity", "antigen binding", "biophysical properties", "design", "efficacy evaluation", "empowerment", "fitness", "improved", "insight", "interest", "neutralizing antibody", "novel", "outcome prediction", "pathogen", "predictive modeling", "pressure", "response", "trafficking", "vaccine development" ], "approved": true } }, { "type": "Grant", "id": "15981", "attributes": { "award_id": "1R21AI190798-01A1", "title": "Detection of Shigella Species in Wastewater - A Pilot Study for Community and Building Scale Wastewater-Based Surveillance of Bacterial 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": 44432, "first_name": "JONATHAN A", "last_name": "GLOCK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-02-03", "end_date": "2028-01-31", "award_amount": 422125, "principal_investigator": { "id": 44436, "first_name": "Anthony T", "last_name": "Maurelli", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3432, "ror": "", "name": "UNIVERSITY OF FLORIDA", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true }, "abstract": "/ Abstract Bacillary dysentery or shigellosis is caused by bacteria of the Shigella species: S. dysenteriae, S. flexneri, S boydii, and S. sonnei. Infections range from mild or asymptomatic to severe bloody diarrhea, so reported prevalence grossly underestimates actual prevalence. Shigellosis is a global public health concern and antimicrobial resistance has compounded the problem. Moreover, shigellosis is also sexually transmitted in the United States, Europe, and other developed countries. Such outbreaks are driven by the emergence of antibiotic resistant strains of S. flexneri infecting men who have sex with men. The objective of this proof-of-concept study is to demonstrate that wastewater-based epidemiology (WBE) using digital PCR to detect pathogen molecular markers can provide a more accurate picture of community prevalence of bacterial pathogens than traditional case reporting. Wastewater surveillance for viral pathogens has been in use for decades and its use to monitor SARS-CoV-2 is now widely applied globally. Analogous methods for wastewater surveillance of bacterial pathogens by digital PCR has lagged. We will develop and validate methods to detect Shigella, an important bacterial agent of diarrheal disease, in wastewater. We will also field test the methods to assess shigellosis prevalence at community and building scale and link the data to the actual population residing in the wastewater collection area. We will provide actionable data to the local health department which can then develop targeted public health interventions. The independent but complementary aims in demonstrating the proof-of-concept are: 1. Develop and validate sensitive, specific, and reproducible WBE methods for detection of Shigella species in wastewater using digital PCR. Three subaims will: 1.1) optimize methods for extraction and detection of Shigella in wastewater using laboratory-grown strains of Shigella species to “spike” authentic wastewater and laboratory prepared “synthetic” wastewater; 1.2) validate molecular targets for differentiation of S. flexneri from S. sonnei in wastewater; and 1.3) culture of Shigella from wastewater to assess antibiotic resistance genotypes and phenotypes. 2. Assess proof-of-concept of WBE as a public health tool for Shigella at community and building scale with emphasis on high risk congregate populations, i.e., day care centers. Two subaims will: 2.1) measure the prevalence of Shigella species at community scale by sampling at the wastewater treatment plant intake and using wastewater flow rate as a population normalization marker; and 2.2) extend shigellosis surveillance to building scale targeting high risk congregate pediatric populations. Strengths of this proposal are the innovative application of WBE to a bacterial pathogen, our method for population normalization, differentiation of Shigella species, prevalence measurement of Shigella species at community and building scale, and the expertise of our multidisciplinary team.", "keywords": [ "2019-nCoV", "Antibiotic Resistance", "Antimicrobial Resistance", "Area", "Automobile Driving", "Bacteria", "Bacterial Infections", "Behavior", "COVID-19 monitoring", "COVID-19 surveillance", "Case Study", "Centers for Disease Control and Prevention (U.S.)", "Childhood", "Collection", "Communities", "County", "Data", "Day center care", "Detection", "Developed Countries", "Development", "Disease", "Disease Outbreaks", "Dysentery", "Effectiveness", "Europe", "Excretory function", "Feces", "Florida", "Foundations", "Future", "Genetic", "Genotype", "Health", "Health Resources", "Hemorrhagic colitis", "Hot Spot", "Individual", "Infection", "Intake", "Intervention", "Laboratories", "Link", "Measles", "Measurement", "Measures", "Methodology", "Methods", "Molecular", "Molecular Analysis", "Molecular Profiling", "Molecular Target", "Monitor", "Pathogen detection", "Patients", "Phenotype", "Pilot Projects", "Plants", "Poliomyelitis", "Population", "Population Surveillance", "Populations at Risk", "Prevalence", "Public Health", "Reporting", "Reproducibility", "Research Proposals", "Sampling", "Sexual Transmission", "Shigella", "Shigella Infections", "Shigella boydii", "Shigella dysenteriae", "Shigella flexneri", "Shigella sonnei", "System", "Techniques", "Testing", "United States", "Universities", "Variant", "Viral", "Work", "detection method", "diarrheal disease", "digital", "experience", "field study", "global health", "high risk", "innovation", "men who have sex with men", "molecular marker", "multidisciplinary", "novel", "pathogenic bacteria", "pathogenic virus", "public health intervention", "resistant strain", "tool", "wastewater epidemiology", "wastewater monitoring", "wastewater samples", "wastewater sampling", "wastewater surveillance" ], "approved": true } }, { "type": "Grant", "id": "15980", "attributes": { "award_id": "1R01AI189659-01A1", "title": "Durable and broad airway immunity through next-generation intranasal boosters", "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": 32831, "first_name": "JENNIFER L", "last_name": "GORDON", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-02-06", "end_date": "2031-01-31", "award_amount": 662465, "principal_investigator": { "id": 44435, "first_name": "David R.", "last_name": "Martinez", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3431, "ror": "", "name": "YALE UNIVERSITY", "address": "", "city": "", "state": "CT", "zip": "", "country": "United States", "approved": true }, "abstract": "Intramuscular SARS-CoV-2 mRNA-LNP do not reliably nor durably elicit respiratory mucosal IgA. Moreover, vaccinated individuals who become infected are more durably protected and this is thought to be mediated by respiratory mucosal IgA. Currently, there are no mucosal respiratory vaccines for human use. We identified a mucosal booster vaccine admixed with a mast cell agonist adjuvant, mastoparan-7, and a toll-like receptor 9 agonist adjuvant, CpG, that elicits durable mucosal IgA. Importantly, mice intranasally boosted with a multivalent nanoparticle vaccine adjuvanted with mastoparan-7 and CpG are protected from bat SARS-like virus challenge. We propose to study the mechanism of mast cell and antigen-presenting cell signaling modulated by this novel mucosal adjuvant combination. We will pursue our central objective which is to understand how mucosal IgA is elicited and maintained following respiratory mucosal vaccination with our exciting universal vaccines to ultimately achieve durable and broadly protective immunity against zoonotic coronaviruses. To achieve this objective, we will complete these aims: Aim 1: Test the hypothesis that mast cells and antigen-presenting cells elicit specific cytokines and chemokines that modulate durable IgA. We propose to study the impact of intranasal boost dose and interval on IgA kinetics and durability. We will also define if the mastoparan-7 and CpG adjuvant combination requires mast cell and antigen presenting cells that signal through CpG via the TLR-9 pathway. We will then define gene expression profiles from respiratory tract mast cells and antigen presenting cells that are activated by mastoparan-7 and CpG and modulate durable mucosal IgA responses. Aim 2: Test the hypothesis that M7/CpG nanoparticle vaccine elicits durable IgA secreting cells and IgA memory B cells in the respiratory tract using lineage-tracing, fluorescent reporter mice pre- immune with common-cold CoV. We will determine how intranasal boosting modulates IgA-secreting plasma cells and IgA memory B cells that home back to the respiratory mucosa in SARS-CoV-2 immune mice and in mice immune against common-cold coronaviruses. We will use cre-lox inducible, IgA-secreting cell and IgA memory B cell fluorescent reporter mice to define how intranasal boosting modulates mucosal IgA immunity. We will also test adjuvant and intranasal safety using a human lymph node organoid model from upper- respiratory tract draining lymph tissue from humans. Aim 3: Test the hypothesis that durable mucosal IgA can protect against transmissible SARS-CoV-2 variants in hamster transmission models and protect against SARS-related coronaviruses. We will determine if the mastoparan-7 and CpG adjuvanted nanoparticle intranasal booster reduces transmission of SARS-CoV-2 variants in hamster models. We will also use IgA knockout mice to determine if IgA is required for protection against SARS-like viruses.", "keywords": [ "2019-nCoV", "Adjuvant", "Agonist", "Antigen Targeting", "Antigen-Presenting Cells", "Antigens", "B-Lymphocytes", "Back", "COVID-19 vaccine", "Cell Degranulation", "Cell secretion", "Chiroptera", "Common Cold", "Coronavirus", "Coupled", "Data", "Disease", "Dose", "Ferritin", "Frequencies", "Gene Expression Profile", "Generations", "Genes", "Goals", "Hamsters", "Health", "Home", "Human", "Immune", "Immune response", "Immune signaling", "Immunity", "Immunobiology", "Immunoglobulin A", "Immunologics", "Intramuscular", "Intranasal Administration", "Kinetics", "Knockout Mice", "Knowledge", "Length", "Lineage Tracing", "Lymph", "Mediating", "Memory B-Lymphocyte", "Messenger RNA", "Middle East Respiratory Syndrome Coronavirus", "Modeling", "Monitor", "Mucosal Immunity", "Mucous Membrane", "Mus", "Organoids", "Pathogenicity", "Pathway interactions", "Patients", "Peptides", "Plasma Cells", "RNA vaccine", "Receptor Signaling", "Reporter", "Respiration", "Respiratory Mucosa", "Respiratory System", "SARS coronavirus", "SARS-CoV-2 transmission", "SARS-CoV-2 variant", "Safety", "Severe Acute Respiratory Syndrome", "Signal Transduction", "TLR9 gene", "Tamoxifen", "Testing", "Upper respiratory tract", "Vaccinated", "Vaccination", "Vaccine Adjuvant", "Vaccinee", "Vaccines", "Virus", "Work", "Zoonoses", "antiviral immunity", "booster vaccine", "chemokine", "coronavirus vaccine", "cross immunity", "cytokine", "experimental study", "gene panel", "human tissue", "lipid nanoparticle", "lymph nodes", "mast cell", "mastoparan", "mucosal vaccination", "mucosal vaccine", "nanoparticle", "next generation", "novel", "novel coronavirus", "pandemic disease", "preclinical safety", "respiratory", "respiratory virus", "response", "single-cell RNA sequencing", "tool", "transmission process", "universal vaccine", "vaccine evaluation", "zoonotic coronavirus" ], "approved": true } } ], "meta": { "pagination": { "page": 1, "pages": 1424, "count": 14236 } } }