Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=2&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=1405&sort=-start_date", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=3&sort=-start_date", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-start_date" }, "data": [ { "type": "Grant", "id": "15775", "attributes": { "award_id": "1R01AI193318-01", "title": "Assessing the mechanisms underlying female sex-predominance in Long COVID", "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": 32597, "first_name": "BROOKE ALLISON", "last_name": "BOZICK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-22", "end_date": "2030-07-31", "award_amount": 913012, "principal_investigator": { "id": 31372, "first_name": "Michael Joseph", "last_name": "Peluso", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32848, "first_name": "Nadia R", "last_name": "Roan", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2635, "ror": "", "name": "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Long COVID, or post-acute sequelae of COVID-19 (PASC), is estimated to occur after ~10% of COVID-19 cases and affects tens of millions of people worldwide. The mechanisms underlying Long COVID remain poorly understood, which hinders the ability to establish effective evidence-based treatments for the condition. One of the most striking observations in the epidemiology of Long COVID is its female sex predominance: women, particularly pre-menopausal women, are much more likely than men to have the condition. In this proposal, we leverage the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort (NCT04362150) – which since April 2020 has recruited >1,000 participants with and without Long COVID – to interrogate the mechanistic basis underlying the increased prevalence of Long COVID in women. Our central hypothesis is that in women with Long COVID, there is an elevated and sustained immune type I IFN (T1IFN) response to SARS-CoV-2 (SCV2) gene products, which in turn diminishes the quality of adaptive immune responses against chronic herpesviruses (EBV, CMV) and SCV2 itself, increases the risk of pathogenic autoantibody responses, and results in overall systemic inflammation and immune dysregulation that is characteristic of Long COVID. We further postulate that both incomplete X chromosome inactivation and sex hormones drive the elevated T1IFN responses in women with Long COVID. In Aim 1, we will subject banked longitudinal blood specimens from women and men from LIINC (including both those with and without Long COVID) to assays that will measure the extent of persistent SCV2, T1IFN responses, the features of adaptive immune responses to persistent viruses associated with Long COVID (SCV2, EBV, CMV), autoantibody responses, and the overall state of inflammation. In Aim 2, we will leverage the LIINC Tissue Biopsy program to obtain paired endometrial and gut biopsies from women with Long COVID, to test the hypothesis that the endometrium is a key site of SCV2 persistence and immune dysregulation during Long COVID. This analysis will be compared to a parallel set of studies using gut specimens from matched men with Long COVID. Finally, Aim 3 will analyze specimens from two clinical trials designed to eliminate SCV2 gene products as treatment for Long COVID. The first of these, performed by Resolve Therapeutics, found that administration of RSLV-132, a catalytically active RNase1 intended to degrade SCV2 RNA, improved Long COVID symptoms in women but not men (NCT04944121). The second, occurring within LIINC, is ongoing (enrollment is complete) and testing the effects of AER002, a monoclonal antibody that directly targets and clears SCV2 protein (NCT05877508). Using specimens from both trials, we will test the notion that SCV2 gene products drive sustained T1IFN responses in women that contribute to Long COVID symptoms. Collectively, our aims will improve our understanding of the mechanisms underlying the female-predominance of Long COVID and improve our overall understanding of the disease. This will be a key step in the identification of evidence-based treatments for both women and men who continue to develop and live with this disabling condition.", "keywords": [ "2019-nCoV", "Acute", "Affect", "Age", "Antibodies", "Antibody Response", "Antigens", "Autoantibodies", "Autoimmunity", "Biological", "Biological Assay", "Biology", "Biopsy", "Biopsy Specimen", "Blood", "Blood specimen", "Body System", "COVID-19", "COVID-19 impact", "COVID-19 prevalence", "Characteristics", "Chronic", "Clinical Trials", "Clinical Trials Design", "Cytomegalovirus", "Data", "Disabling condition", "Disease", "Disproportionately impacts women", "Endometrial", "Endometrium", "Enrollment", "Epidemiology", "Estradiol", "Evidence based treatment", "Exhibits", "Fatigue", "Female", "Functional impairment", "Genes", "Genitourinary system", "Gonadal Steroid Hormones", "Health", "Herpesviridae", "High Prevalence", "Human Herpesvirus 4", "Immune", "Immune System Diseases", "Immune response", "Immunity", "Individual", "Infection", "Inflammation", "Inflammatory", "Inflammatory Response", "Interferons", "Intervention", "Intervention Trial", "Link", "Long COVID", "Longitudinal Studies", "Measurement", "Measures", "Monoclonal Antibodies", "Nature", "Observational epidemiology", "Organ", "Outpatients", "Paper", "Participant", "Pathway interactions", "Persons", "Phenotype", "Post-Acute Sequelae of SARS-CoV-2 Infection", "Premenopause", "Prevalence", "Progesterone", "Proteins", "Publishing", "RNA", "Research Infrastructure", "Risk", "SARS-CoV-2 infection", "SARS-CoV-2 inhibitor", "Sex Differences", "Signal Transduction", "Site", "Specimen", "Symptoms", "T cell response", "TLR7 gene", "Testing", "Testosterone", "Therapeutic", "Tissues", "Vaccination", "Viral", "Virus", "Virus Diseases", "Woman", "Women's prevalence", "X Inactivation", "acute COVID-19", "adaptive immune response", "brain fog", "cohort", "common symptom", "design", "experience", "female reproductive tract", "gene product", "improved", "interest", "longitudinal analysis", "men", "mucosal site", "novel coronavirus", "pathogenic autoantibodies", "programs", "prospective", "randomized trial", "recruit", "repository", "response", "sex", "single-cell RNA sequencing", "systemic inflammatory response", "therapy design", "transcriptome", "women's outcomes" ], "approved": true } }, { "type": "Grant", "id": "15751", "attributes": { "award_id": "1R01AI184716-01A1", "title": "Explore a key nucleotide synthesis enzyme to develop a broad-spectrum antiviral therapy.", "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": "2025-08-21", "end_date": "2030-07-31", "award_amount": 831235, "principal_investigator": { "id": 32809, "first_name": "Pinghui", "last_name": "Feng", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 25475, "first_name": "Chao", "last_name": "Zhang", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2622, "ror": "", "name": "UNIVERSITY OF SOUTHERN CALIFORNIA", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Title: Explore a key nucleotide synthesis enzyme to develop a broad-spectrum antiviral therapy Co-PI: Pinghui Feng (contact) and Chao Zhang With highly infectious viruses rapidly emerging and re-emerging (such as SARS-Coronavirus, influenza virus and drug-resistant herpes simplex viruses), the human society is challenged with limited options to treat diseases associated with these human viruses. In fact, antiviral therapies that effectively thwart the infection of a broad spectrum of viral pathogens are long sought in the antiviral community. In studying viral immune evasion, we have discovered that diverse viruses, including SARS- CoV-2, herpes simplex virus 1 (HSV-1) and influenza A virus (IAV), activate a key nucleotide synthesis enzyme not only to fuel nucleotide supply, but also block antiviral inflammatory cytokine production, thus efficiently promoting viral replication. We aim to target the key nucleotide synthesis enzyme for inhibition, which will deplete nucleotide supply and restore antiviral immune response to impede their replication. To achieve this goal, we have engineered conditional knockout and knockin mouse strains that will enable the genetic interrogation of the enzyme- mediated evasion of inflammatory response and metabolic reprogramming during the infection of SARS-CoV-2, IAV and HSV-1. Teaming up with a chemical biologist (Dr. Chao Zhang, University of Southern California), we have synthesized a library of small molecules and characterized specific inhibitors of the nucleotide enzyme. Furthermore, we will collaborate with a structural biologist (Dr. Santiago Ramon-Maiques, Instituto de Biomedicina de Valencia, Spain) to perform structure-activity relationship (SAR) analysis to further improve the lead small-molecule inhibitors. This study will provide a proof-of-concept to target a nucleotide synthesis enzyme in an effort to combat the infection of key human viral pathogens.", "keywords": [ "2019-nCoV", "Amino Acids", "Anti-viral Therapy", "Aspartate", "COVID-19 pandemic", "California", "Carbamoyl Transferases", "Carbamyl Phosphate", "Cell Line", "Cells", "Chemicals", "Coenzymes", "Collaborations", "Communities", "DNA Virus Infections", "DNA Viruses", "Data", "Dihydroorotase", "Disease", "Drug Kinetics", "Drug resistance", "Engineering", "Enzyme Inhibition", "Enzymes", "Gene Expression", "Genes", "Genetic", "Glutamine", "Glycoproteins", "Goals", "Herpesviridae", "Herpesvirus 1", "Homeostasis", "Host Defense", "Human", "Immune Evasion", "Immune response", "In Vitro", "Infection", "Infectious Agent", "Inflammatory", "Inflammatory Response", "Influenza A virus", "Knock-in Mouse", "Knockout Mice", "Laboratories", "Lead", "Libraries", "Ligase", "Lung", "Mediating", "Medical", "Medicine", "Metabolic", "Metabolism", "Modernization", "Mouse Strains", "Mus", "NF-kappa B", "Normal Cell", "Nucleotides", "Production", "Proliferating", "Property", "Proteins", "Pyrimidine", "RNA Viruses", "Role", "SARS coronavirus", "SARS-CoV-2 infection", "Shunt Device", "Signaling Protein", "Simplexvirus", "Societies", "Spain", "Structural Biologist", "Structure-Activity Relationship", "Tissues", "Translating", "Universities", "Viral", "Virus", "Virus Diseases", "Virus Replication", "Work", "aerobic glycolysis", "antiviral drug development", "cancer cell", "cellular targeting", "combat", "conditional knockout", "cytokine", "cytotoxicity", "deamidation", "design", "genetically modified cells", "glutamine analog", "improved", "influenzavirus", "inhibitor", "insight", "interest", "nucleotide metabolism", "pathogen", "pathogenic virus", "pharmacologic", "programs", "prototype", "recruit", "small molecule", "small molecule inhibitor", "small molecule libraries", "transcription factor" ], "approved": true } }, { "type": "Grant", "id": "15750", "attributes": { "award_id": "1R15AI191143-01A1", "title": "RNA homodimerization strand displacement pathways to extended duplexes: Atomistic details for a mechanistic paradigm to identify unique antiviral targets for current and emerging viral pandemics", "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": 32806, "first_name": "DAVID JOSEPH", "last_name": "MCDONALD", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-21", "end_date": "2028-07-31", "award_amount": 507121, "principal_investigator": { "id": 32807, "first_name": "JEFFREY D", "last_name": "EVANSECK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2621, "ror": "", "name": "DUQUESNE UNIVERSITY", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "Kissing complexes (KC) and extended duplexes (ED) represent dynamic RNA structures whose interconversion is an example of strand displacement reactions that has been implicated in playing vital roles in several viruses, influencing a broad spectrum of biochemical processes including genome packaging, viral recombination, and host-pathogen interactions. However, the structural, dynamic, and energetic details on how these interconversions occur are virtually unknown yet are vital in our novel approach of identifying and characterizing previously unconsidered meta-stable pathway states to inspire future antiviral and drug resistance development. Overcoming significant challenges that hamper meaningful modelling of RNA and dimers, and associated interconversion pathways necessitate judicious choice of computational techniques and integration with experimental data across physiologically relevant timescales. Our overarching hypothesis is that by leveraging the limited kinetic and thermodynamic data reported on RNA transition pathway systems, including the human immunodeficiency virus 1 (HIV-1) dimer initiation site (DIS) and model complexes based on the bacterial E. coli DsrA-rpoS RNA-mRNA regulatory complex, a general paradigm will be developed for other known RNA dimerization systems, such as SARS-CoV, SARS-CoV-2, HCV, and future emerging RNA viruses requiring novel antiviral therapies. To address our hypothesis, we first employ a unique approach to establish the unbiased structure and dynamics of RNA structures representing both pathway endpoints of each strand displacement reaction, such as KC to ED (Aim I). Confidence in structural predictions for systems without experimental structures is engendered by comparing computations against HIV-1 DIS crystallographic structures. We next apply a minimum energy pathway technique with and without protein chaperones to identify meta-stable states (Aim II). Reliability of the method is evaluated against the kinetic and thermodynamic data reported for the KC to ED interconversion for the E. coli DsrA-rpoS RNA-mRNA regulatory complex. Finally, as a proof of concept, we will screen RNA-binding molecules and antisense oligonucleotides against identified meta-stable intermediates along the pathways (Aim III). Aligned with NIH/R15 goals, we will train undergraduates to understand the capabilities, limitations, and errors of experimental and computational chemistry to craft ultimately a seamless research approach. Our training objective is to deliver a quality research experience that motivates undergraduates to achieve their highest potential and best prepare them for scientific research and discovery. The intent is to attract and retain the nation’s diverse student talent pool, having the consequence of enriching and diversifying the U.S. workforce by adding experts in the field of biomedical chemistry. The expected scientific outcomes are to unlock novel physical insights into strand displacement reactions and provide a foundation for targeted drug design and therapeutic interventions for drug resistance of HIV-1, SARS-CoV2, and HCV viruses of current", "keywords": [ "2019-nCoV", "Address", "Anti-viral Agents", "Anti-viral Therapy", "Anti-viral resistance", "Antisense Oligonucleotides", "Bacteria sigma factor KatF protein", "Benchmarking", "Binding", "Biochemical", "Biochemical Process", "Biological", "Biophysics", "Chemistry", "Complex", "Computational Technique", "Computer software", "Computing Methodologies", "Conserved Sequence", "Coronavirus", "Crystallography", "Data", "Data Reporting", "Dimerization", "Docking", "Drug Combinations", "Drug Design", "Drug Targeting", "Drug resistance", "Elasticity", "Elements", "Escherichia coli", "Foundations", "Free Energy", "Future", "Generations", "Genetic Recombination", "Genome", "Geometry", "Goals", "HIV-1", "Health", "Hepatitis C", "Hepatitis C virus", "Homodimerization", "Immune response", "Investments", "Kinetics", "Knowledge", "Life", "Life Cycle Stages", "Messenger RNA", "Methodology", "Methods", "Modeling", "Molecular Chaperones", "Nucleocapsid", "Oligonucleotides", "Outcome", "Pathway interactions", "Pharmaceutical Preparations", "Pharmacologic Substance", "Physiological", "Play", "Process", "Proteins", "Publications", "RNA", "RNA Binding", "RNA Viruses", "RNA-targeting therapy", "Reaction", "Reporting", "Research", "Research Personnel", "Resistance", "Role", "SARS coronavirus", "Sampling", "Signal Transduction", "Site", "Small RNA", "Structure", "Students", "System", "Talents", "Techniques", "Testing", "Therapeutic Intervention", "Thermodynamics", "Training", "United States National Institutes of Health", "Validation", "Viral", "Viral Drug Resistance", "Virus", "Work", "X-Ray Crystallography", "antiviral drug development", "comparative", "computational chemistry", "dimer", "drug resistance development", "experience", "experimental study", "genomic RNA", "graduate student", "insight", "interest", "novel", "novel strategies", "pathogen", "public health relevance", "simulation", "small molecule", "student training", "trustworthiness", "undergraduate student", "viral RNA", "viral pandemic", "virtual" ], "approved": true } }, { "type": "Grant", "id": "15781", "attributes": { "award_id": "1R01AI183979-01A1", "title": "Expanding access and impact of tuberculosis preventive therapy: Community-friendly delivery and monitoring of TPT to improve uptake and reduce TB transmission", "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": 32562, "first_name": "KAREN A", "last_name": "LACOURCIERE", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-19", "end_date": "2030-07-31", "award_amount": 690538, "principal_investigator": { "id": 28321, "first_name": "ADRIENNE E", "last_name": "SHAPIRO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2645, "ror": "", "name": "UNIVERSITY OF WASHINGTON", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "Enter the text here that is the new abstract information for your application. International and Kenyan guidelines recommend TB preventive therapy (TPT) for people with HIV (PWH) and other people at high risk for TB, including close contacts of people with TB. Despite the evidence for reduced morbidity and mortality for people with HIV (PWH) who receive TPT, and guidelines recommending use, there remains a substantial gap between people recommended to receive and people who actually receive and complete a course of TPT. The 2022 WHO Global TB Report highlighted the growing gap in access and provision of TPT, which has been aggravated by the COVID-19 pandemic. Bridging this gap is a Kenyan and global priority. With the recent availability and evidence for newer, shorter regimens of TPT, a transformation of HIV care delivery models (in part forced by the COVID-19 pandemic) and evolving national guidelines for TPT, it is increasingly urgent to explore new person-friendly models of TPT delivery to inform programmatic guidance that results in greater uptake, adherence, and completion of TPT. HIV care transformed to adopt “differentiated service delivery” (DSD) models, which encourage community-delivered care, infrequent clinic/facility visits, multi- month dispensing, limited laboratory monitoring, and task-shifted treatment models to deliver comprehensive HIV care to stable adults in community settings. These successful models for differentiated HIV care delivery may be able to be adapted to include TPT. The availability of safe, effective, short-course TPT (i.e. 3HP, 3HR) with limited monitoring requirements suggests that similar community-based and multi-month dispensing models may be adapted to scale essential TPT to populations who most need it, including PWH, young child contacts, and all household contacts of people with TB. We will explore two approaches of adapting HIV differentiated services to TB prevention. We hypothesize that people who receive differentiated TPT delivery have higher rates of completion of a course of TPT than people who receive standard-of-care clinic-based TPT. We will 1) conduct a randomized controlled trial of DSD care (multi-month dispensing) vs. clinic standard-of-care TPT delivery in two priority populations for TPT in Kenya: household contacts of people with TB and PWH, 2) investigate the impact of DSD TPT on household and community TB transmission with follow-up testing and mathematical modeling, and 3) examine preferences, barriers and facilitators of TPT completion and TPT implementation using qualitative research. Together, this research will establish the foundation for implementation studies of optimized patient and community-friendly, differentiated TPT delivery approaches to increase TPT uptake and completion in Kenya and ultimately decrease morbidity, transmission, and mortality from TB.", "keywords": [ "Adherence", "Adopted", "Adult", "Adverse effects", "Biological Assay", "COVID-19 pandemic", "Caring", "Cessation of life", "Child", "Client", "Clinic", "Clinical", "Communicable Diseases", "Communities", "Dose", "Drug resistance in tuberculosis", "Eligibility Determination", "Focus Groups", "Foundations", "Friends", "Goals", "Guidelines", "HIV", "HIV/TB", "Health system", "Home", "Household", "Incidence", "Individual", "Interferon Type II", "International", "Interview", "Kenya", "Laboratories", "Measures", "Methodology", "Methods", "Modeling", "Monitor", "Morbidity - disease rate", "Patients", "Persons", "Pharmaceutical Preparations", "Population", "Prevention", "Preventive therapy", "Qualitative Research", "Randomized", "Randomized Controlled Trials", "Recommendation", "Regimen", "Reporting", "Research", "Schedule", "Service delivery model", "Services", "Testing", "Text", "Time", "Toxic effect", "Travel", "Treatment Protocols", "Tuberculosis", "Tuberculosis diagnosis", "Visit", "World Health Organization", "care delivery", "community setting", "cost", "experience", "follow-up", "gaps in access", "health care delivery", "high risk", "immunoreactivity", "implementation strategy", "implementation study", "improved", "informant", "innovation", "isoniazid", "mathematical model", "mortality", "person centered", "pill", "preference", "prevent", "preventable death", "rifapentine", "scale up", "screening", "service delivery", "standard of care", "supply chain", "transmission process", "treatment as usual", "trial comparing", "uptake" ], "approved": true } }, { "type": "Grant", "id": "15748", "attributes": { "award_id": "1R21AI193903-01", "title": "Identification and characterization of the class I and class II MHC molecules of the Syrian hamster to enable advanced studies of T cell 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": 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": "2025-08-19", "end_date": "2027-07-31", "award_amount": 486200, "principal_investigator": { "id": 32804, "first_name": "Teresa P", "last_name": "DiLorenzo", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2619, "ror": "", "name": "ALBERT EINSTEIN COLLEGE OF MEDICINE", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "The Syrian hamster (Mesocricetus auratus) is a valuable model for the study of many RNA viruses, including SARS-CoV-2, as well as numerous other diseases relevant to human health. T cells are an important component of SARS-CoV-2-specific adaptive immunity, and they represent a key potential correlate of immunity or immunopathology in viral diseases in general. Remarkably, T cell immunity cannot be readily evaluated in Syrian hamsters at present, because their MHC molecules have not yet been identified. The lack of knowledge regarding the identity of the MHC molecules of Syrian hamsters has limited the ability of the model to support advanced investigations of cellular immunity in the response to human pathogens and vaccines. Filling this knowledge gap will be necessary to fully realize the promise of the Syrian hamster as an animal model for human diseases and is the primary objective of our proposed work. As a result of our analysis of gene structure, order, and position in the Syrian hamster genome, coupled with comparison to the mouse genome, we have identified plausible candidates for the genes encoding the classical class I and class II MHC molecules of the research Syrian hamster. We also discovered that select monoclonal antibodies (mAbs) raised to mouse MHC molecules cross-react with splenocytes of Syrian hamsters. In Aim 1, we will generate a group of cell lines, each of which will express a single candidate hamster MHC molecule. These “mono-allelic” cell lines will allow us to characterize the cross-reactivity of the anti-mouse mAbs in terms of which hamster MHC candidates they are recognizing, thus enabling the tentative identification of the candidates as genuine MHC molecules. We will verify that the cell lines can present peptides to stimulate T cells from infected or vaccinated hamsters, using SARS- CoV-2 as a model system. An important practical advance to arise from this work will be the ability to create peptide/MHC tetramers to follow T cell responses in hamsters. In Aim 2, we will define binding motifs for the hamster MHC molecules from the sequences of their natural ligands and create binding matrices to permit the identification of candidate T cell epitopes for pathogens of interest. This will permit the confirmation of the hamster candidates as true MHC molecules capable of presenting diverse arrays of peptides. Primary anchor residues and the most common peptide lengths will also be revealed. The sequences of the eluted peptides will be used to develop binding matrices that will permit prediction of candidate T cell antigens and epitopes for any current or emerging pathogen that can be modeled in the Syrian hamster. Our project will achieve the identification and functional characterization of the class I and class II MHC molecules of the Syrian hamster, enabling advanced studies of T cell immunity and greatly enhancing its utility as a model for diseases relevant to human health.", "keywords": [ "2019-nCoV", "Achievement", "Animal Model", "Animals", "Antigens", "Binding", "Biological Models", "CD4 Positive T Lymphocytes", "CD8-Positive T-Lymphocytes", "COVID-19", "Candidate Disease Gene", "Cause of Death", "Cavia", "Cell Line", "Cell surface", "Cells", "Cellular Immunity", "Characteristics", "Complex", "Cotton Rats", "Coupled", "Cross Reactions", "Disease", "Elements", "Epitopes", "Evaluation", "Ferrets", "Flow Cytometry", "Gene Structure", "Genes", "Genetic Transcription", "Genome", "Goals", "Hamsters", "Health", "Histocompatibility Antigens Class II", "Human", "Immune system", "Immunity", "Infection", "Investigation", "Knowledge", "Length", "Ligands", "Literature", "Major Histocompatibility Complex", "Mass Spectrum Analysis", "Mesocricetus auratus", "Modeling", "Monoclonal Antibodies", "Mus", "Pattern", "Peptides", "Phenotype", "Positioning Attribute", "RNA Viruses", "Reagent", "Research", "Splenocyte", "Study models", "Syria", "T cell response", "T-Cell Receptor", "T-Lymphocyte", "T-Lymphocyte Epitopes", "Time", "Transplantation", "Vaccinated", "Vaccination", "Vaccines", "Viral", "Virus", "Virus Diseases", "Work", "adaptive immunity", "beta-2 Microglobulin", "candidate identification", "cross reactivity", "disease model", "emerging pathogen", "fighting", "human disease", "human pathogen", "immunoaffinity chromatography", "immunopathology", "interest", "mouse genome", "pathogen", "protein complex", "response", "vaccine development", "vaccine-induced immunity" ], "approved": true } }, { "type": "Grant", "id": "15792", "attributes": { "award_id": "1R21AI193885-01", "title": "UTS-1401 as a Medical Countermeasure to H-ARS Consequent to a Radiation Mass Casualty", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "NIH Office of the Director" ], "program_reference_codes": [], "program_officials": [ { "id": 32879, "first_name": "LANYN P", "last_name": "TALIAFERRO", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-18", "end_date": "2027-07-31", "award_amount": 157000, "principal_investigator": { "id": 32877, "first_name": "Stephen L", "last_name": "Brown", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32878, "first_name": "FREDERICK Augustus", "last_name": "VALERIOTE", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2633, "ror": "", "name": "HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true }, "abstract": "Abstract: Our long term objective is to develop a new class of radiation mitigating agents with attractive chemical, physical and biological characteristics required to be an effective drug that can be distributed widely. We have identified a small molecule, UTS-1401 [5-(methylthiomethyl) isoxazole-3-carboxylic acid] which demonstrates mitigation of hematopoietic stem cell death when administered at either 24h or 48h following whole body irradiation (WBI). Using the endogenous spleen colony assay, we demonstrated a mitigating effect in that the colony number with and without UTS-1401 was 3.5 ± 0.4 for a 24h interval and 2.3 ± 0.5 for a 48h interval. We have recently demonstrated a significant radioprotection for both mouse survival and hematopoietic stem cells for this compound when administered up to 72h before irradiation (Valeriote et al, Radiation Research, 202:16- 25, 2024). In this application, we propose to further examine solely the mitigating effect on the hematopoietic acute radiation syndrome (H-ARS) using survival as the endpoint in specific aim 1. Groups of Swiss mice will receive a series of graded doses of WBI (in 0.5 Gy increments) around the LD50 for this syndrome (approximately 7.5 Gy in females and 8.5 Gy in males) with and without the administration of 150 mg/kg UTS-1401. The single dose of UTS-1401 being used in all studies is the highest dose administrable due to its aqueous solubility (in tartrate buffered saline). The radiation mitigation factors will be calculated as the ratio of the LD50 for radiation plus UTS-1401 versus that for radiation alone. The degree of mitigation will be examined at 24, 48 and 72 h following WBI to determine the radiation mitigation fraction as a function of time after radiation exposure. Three routes of drug delivery, intravenous (iv), oral, and subcutaneous (sc), will be examined and compared. Radiation will be delivered by 16 MeV electrons from a Linac. In specific aim 2, we will examine the pharmacokinetics (PK) for 150 mg/kg UTS-1401 comparing the iv, oral, and sc routes to obtain a determination of both the drug kinetics and bioavailability. The AUC values will be correlated with the extent of mitigation. For both specific aims, both male and female mice will be separately studied. The results from these studies are expected to demonstrate an effective first-in-class compound, UTS-1401, which has a small molecular weight, is chemically stable, nontoxic, aqueous soluble and inexpensive with H-ARS radiation mitigating properties which extend for a number of days following WBI. The mechanism studies (not proposed here) are expected to demonstrate UTS- 1401 as a new class of agents for mitigating the cytokine storm consequent to the irradiation.", "keywords": [ "Accidents", "Acute", "Address", "Animal Model", "Animals", "Biologic Characteristic", "Biological", "Biological Assay", "Biological Availability", "Biotechnology", "Blood", "Bone Marrow", "Buffers", "Carboxylic Acids", "Cell Death", "Cells", "Chemicals", "Chernobyl Nuclear Accident", "China", "Clinical", "Conflict (Psychology)", "Cyclic GMP", "Data", "Development", "Dose", "Drug Delivery Systems", "Drug Kinetics", "Drug Stability", "Electromagnetics", "Electrons", "Employee", "Equipment and supply inventories", "Exposure to", "FDA approved", "Federal Government", "Female", "Fibrosis", "Follow-Up Studies", "Formulation", "Fukushima", "Geographic Distribution", "Goals", "Growth Factor", "Hematopoietic", "Hematopoietic System", "Hematopoietic stem cells", "Hospitals", "Individual", "Industry", "Inflammation", "Inflammatory", "Injury", "International", "Intervention", "Intravenous", "Ionizing radiation", "Iran", "Isoxazoles", "Israel", "Korea", "Lethal Dose 50", "Location", "Molecular Weight", "Mus", "North Korea", "Nuclear", "Nuclear Accidents", "Nuclear Weapon", "Oral", "Oral Administration", "Organ", "Pharmaceutical Preparations", "Pharmacologic Substance", "Pharmacology and Toxicology", "Phase", "Phase I Clinical Trials", "Physiologic pulse", "Procedures", "Process", "Property", "Radiation", "Radiation Accidents", "Radiation Protection", "Radiation Toxicity", "Radiation exposure", "Refrigeration", "Research", "Rotation", "Route", "Russia", "Saline", "Schedule", "Series", "Solubility", "South Korea", "Spleen", "Swiss Mice", "Syndrome", "System", "Taiwan", "Tartrates", "Temperature", "Terrorism", "Time", "Tissues", "Ukraine", "United States National Aeronautics and Space Administration", "Vomiting", "War", "Whole-Body Irradiation", "Work", "aqueous", "chemical stability", "cost effective", "cytokine", "cytokine release syndrome", "design", "drug development", "efficacy study", "expiration", "irradiation", "male", "manufacture", "mass casualty", "medical countermeasure", "novel", "product development", "radiation countermeasure", "radiation mitigation", "radiation response", "radioprotected", "research study", "safety study", "scale up", "small molecule", "subcutaneous", "success" ], "approved": true } }, { "type": "Grant", "id": "15749", "attributes": { "award_id": "1R21AI188683-01A1", "title": "Contribution of adipose tissue immune cells to Influenza 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": 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": "2025-08-18", "end_date": "2027-07-31", "award_amount": 240750, "principal_investigator": { "id": 32805, "first_name": "Senad", "last_name": "Divanovic", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2620, "ror": "", "name": "CINCINNATI CHILDRENS HOSP MED CTR", "address": "", "city": "", "state": "OH", "zip": "", "country": "United States", "approved": true }, "abstract": "Epidemiological evidence establishes obesity as an independent risk factor for increased severity of viral respiratory pneumonias including influenza virus infection. Dysregulated systemic and tissue inflammation is critical to the pathogenesis of both influenza- and obesity-comorbidities. However, the critical processes that govern increased influenza severity in obesity remain undefined. The expansion of white adipose tissue (WAT) along with activation of WAT-residing immune cells inflammation promotes tissue/organ damage severity in obesity. Of note, WAT depots differ in their anatomical location and function—characteristics that are directly linked with the pathogenesis of disease-impacted organs. Using a model that combines obesity and influenza A virus (IAV) infection we reported that obese mice exhibit in greater mortality and worsened lung inflammation and tissue pathology compared to lean controls. Focusing on immune cells, we showed that IAV infection changes epididymal WAT (eWAT; a depot distal to the lungs) and lung immune cell composition and function, and favors accrual of a macrophage (MØ) subset in the lungs that shares a transcriptomic signature with eWAT residing inflammatory MØs. However, although transfer of eWAT MØ from obese into lean IAV infected mice amplified host immune cell infiltration to the lungs, it was not sufficient to increase influenza severity. Thus, eWAT MØ, although important, either do not possess the full extent of pathogenic traits or other WAT-residing immune cells are dominant contributors to influenza severity in obesity. Importantly, the presence of thoracic WAT (tWAT; a depot that is proximal to the lungs) was reported in individuals living with obesity and in obese mice. Notably, adipocytes and MØ within tWAT support IAV replication and produce proinflammatory factors during IAV infection. However, whether the character and function of tWAT and eWAT immune cells, including MØ, differs during IAV infection has not been studied. Our preliminary studies comparing tWAT and eWAT immune cells show that: (i) transfer of tWAT immune cells from obese mice into IAV infected lean mice induces mortality; (ii) tWAT is highly enriched in phenotypically distinct immune cell types; and (iii) tWAT MØ exhibit greater ability to produce proinflammatory cytokines relevant in influenza pathogenesis. Together, our novel data and existing literature support the overarching hypothesis that tWAT MØ become progressively more proinflammatory during obesity and IAV infection, and that activation of tWAT MØ unique pathogenic traits is sufficient to increases influenza severity. To test this hypothesis, we will: (1) Determine cellular traits of tWAT immune cells in obesity and influenza severity; and (2) Determine pathological processes whereby tWAT macrophages exacerbate influenza severity. Given the global increase in the incidence of obesity and viral pneumonias (e.g., Influenza, SARS-CoV-2) our high-risk/high-reward proposal will provide keen insights into previously unexplored processes that govern inflammation-associated disease severity in obesity.", "keywords": [ "2019-nCoV", "Adipocytes", "Adipose tissue", "Adoptive Transfer", "Adult", "Affect", "Anatomy", "Blood", "Cardiovascular Diseases", "Cell Physiology", "Cells", "Cessation of life", "Characteristics", "Chest", "Chronic Kidney Failure", "Communicable Diseases", "Crohn's disease", "Data", "Development", "Disease", "Distal", "Enzyme-Linked Immunosorbent Assay", "Epidemiology", "Evolution", "Exhibits", "Exploratory/Developmental Grant", "Flow Cytometry", "Future", "Gene Modified", "Goals", "Heart", "Histopathology", "Hospitalization", "Immune", "Incidence", "Individual", "Infection", "Inflammation", "Inflammatory", "Influenza", "Influenza A virus", "Kidney", "Link", "Literature", "Location", "Lung", "Lung Diseases", "Macrophage", "Modeling", "Mus", "Obese Mice", "Obesity", "Organ", "PTPRC gene", "Pathogenesis", "Pathogenicity", "Pathologic Processes", "Pathology", "Persons", "Phenotype", "Pneumonia", "Preventive", "Process", "Production", "Public Health", "Pulmonary Inflammation", "Pulmonary Pathology", "Reporting", "Risk", "Risk Factors", "Severities", "Severity of illness", "Shapes", "Source", "Structure of parenchyma of lung", "Testing", "Therapeutic", "Thinness", "Thoracic cavity structure", "Tissues", "Viral", "Viral Load result", "Viral Pneumonia", "Virus Diseases", "Virus Replication", "Visceral", "Wild Type Mouse", "Youth", "cell type", "clinically significant", "comorbidity", "cytokine", "experimental study", "high reward", "high risk", "immune cell infiltrate", "immune function", "improved", "influenza infection", "insight", "mortality", "novel", "pandemic disease", "pulmonary function", "respiratory", "systemic inflammatory response", "trait", "transcriptome", "transcriptomics" ], "approved": true } }, { "type": "Grant", "id": "15764", "attributes": { "award_id": "1R21AI187979-01A1", "title": "Development of a stable mRNA prophylactic vaccine against SARS-CoV-2 omicron variant", "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": "2025-08-18", "end_date": "2027-07-31", "award_amount": 161500, "principal_investigator": { "id": 32832, "first_name": "Yongbin", "last_name": "Liu", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32833, "first_name": "Junhua", "last_name": "Mai", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2632, "ror": "", "name": "METHODIST HOSPITAL RESEARCH INSTITUTE", "address": "", "city": "", "state": "TX", "zip": "", "country": "United States", "approved": true }, "abstract": "Infectious disease remains one of the leading causes of illness and mortality worldwide. The recent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) led to widespread illness and death, disrupting public health and economy. It has been successfully mitigated thanks to the development and global application of the novel messenger RNA (mRNA) vaccine technology. While mRNA vaccines have offered significant protection, the high mutation rate of SARS-CoV-2 necessitates ongoing development of updated vaccines to combat new variants. While mRNA vaccines have shown remarkable effectiveness against COVID-19 by stimulating both humoral and cellular immune responses, the main limitation lies in the inherent instability of mRNAs at normal conditions without protection. Therefore, current mRNA and mRNA formulations require ultralow temperatures for storage and transportation. Recognizing the instability challenge, we proposed to develop a novel “RNA-plex” technology, which uses an “carrier-base” polymer to bind to mRNA molecules, preventing them from degradation in fridge or room temperature during storage. It significantly reduces the transportation and distribution costs, and makes mRNA vaccines more accessible globally, especially in areas with limited cold chain facilities. Notably, this mRNA protection technology can universally shield various mRNAs, is compatible with multiple delivery systems, and significantly enhances mRNA translation in cells, suggesting its promising potential for diverse therapeutic and research applications. In this proposal, we will apply this mRNA stabilization technology named “RNA-plex” in the development of stable and efficient vaccines for SARS-CoV-2 prevention. Specifically, we will optimize the composition and formulation of RNA-plex to maximize its protective efficacy for SARS-CoV-2 omicron variant spike protein mRNA. Next, we will apply it in preparing prophylactic lipid nanoparticle (LNP) mRNA vaccines with high stability, enhanced antigen translation efficiency, and superior vaccination effectiveness compared to conventional approaches against emerging viral threats, using the recent SARS-CoV-2 omicron variant XBB.1.5 as a proof-of-principle model. Specific Aims: Aim 1. Stabilization of SARS-CoV-2 omicron variant mRNA using RNA-plex technology and develop an LNP mRNA vaccine. Aim 2. Evaluate the efficacy of LNP-RNA-plex vaccine in eliciting immune responses and protection against SARS-CoV-2 Omicron variant.", "keywords": [ "2019-nCoV", "Address", "Adverse effects", "Affect", "Algorithms", "Animal Model", "Antibody titer measurement", "Antigens", "Area", "Aspartate", "B-Lymphocytes", "Base Composition", "Behavior", "Binding", "Biological", "Biological Assay", "Biology", "COVID-19", "COVID-19 pandemic", "COVID-19 vaccine", "Cells", "Cessation of life", "Charge", "Circular Dichroism", "Codon Nucleotides", "Cold Chains", "Communicable Diseases", "Complex", "Cryopreservation", "Dependence", "Development", "Differential Scanning Calorimetry", "Dissociation", "Effectiveness", "Electrostatics", "Endosomes", "Ensure", "Enzyme-Linked Immunosorbent Assay", "Formulation", "Glutamates", "Goals", "Hydrogen Bonding", "Hydrolysis", "Immune response", "Immunization", "Individual", "Infrastructure", "K-18 conjugate", "Knowledge", "Length", "Logistics", "Messenger RNA", "Methods", "Modality", "Modeling", "Modification", "Mutation", "Names", "Nucleotides", "Outcome", "Performance", "Phosphorus", "Poly(A) Tail", "Polymers", "Prevention", "Preventive vaccine", "Proteins", "Public Health", "RNA", "RNA Degradation", "RNA Sequences", "RNA Stability", "RNA vaccine", "Research", "Ribonucleases", "Ribose", "Ribosomal Frameshifting", "Ribosomes", "SARS-CoV-2 B.1.1.529", "Structure", "Surface Plasmon Resonance", "System", "T cell response", "Techniques", "Technology", "Temperature", "Testing", "Therapeutic", "Toxic effect", "Transgenic Mice", "Translations", "Transportation", "Update", "Vaccination", "Vaccines", "Variant", "Viral", "Western Blotting", "base", "biodegradable polymer", "booster vaccine", "circular RNA", "cold temperature", "combat", "compare effectiveness", "cost", "design", "efficacy evaluation", "hydroxyl group", "improved", "in vivo monitoring", "innovation", "lipid nanoparticle", "mRNA delivery", "mortality", "mouse model", "novel", "nucleobase", "phrases", "preservation", "prevent", "prophylactic", "protective efficacy", "success", "therapeutic RNA", "translation assay", "vaccine access", "vaccine efficacy", "vaccine formulation", "vaccine platform" ], "approved": true } }, { "type": "Grant", "id": "15759", "attributes": { "award_id": "1R01AI175536-01A1", "title": "ACE2 immunodecoys for long-lasting immunoprophylaxis against sarbecovirus and merbecoviruses that target human ACE2", "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": "2025-08-18", "end_date": "2029-07-31", "award_amount": 2937578, "principal_investigator": { "id": 32825, "first_name": "Samuel", "last_name": "Lai", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32826, "first_name": "RAYMOND J", "last_name": "PICKLES", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2628, "ror": "", "name": "UNIV OF NORTH CAROLINA CHAPEL HILL", "address": "", "city": "", "state": "NC", "zip": "", "country": "United States", "approved": true }, "abstract": "While vaccines are readily available for SARS-CoV-2, there continues to be significant demand for prophylaxis that are potent and not at risk for viral escape to better protect vulnerable populations. In addition, there is emerging evidence that a number of bat sarbecoviruses and merbecoviruses can use human ACE2 (hACE2) as an entry receptor to infect human cells. Thus, there is also a need to advance effective immunoprophylaxis to protect against such zoonotic coronaviruses with pandemic potential. We have previously advanced an ACE2-immunodecoy as treatment for SARS-CoV-2 infections. Instead of the common approach pursued by many investigators to affinity mature ACE2 to enhance binding to SARS-CoV-2 Spike, we instead sought to optimize the linkage between the extracellular fragment of human ACE2 and IgG1-Fc (ALFc) to promote improved bivalent binding to SARS-CoV-2 Spike. Similar to other ACE2- decoys, ALFc is not susceptible to viral escape. Unlike other ACE2-decoys, the preservation of the full human ACE2 sequence means ALFc is likely active against all ACE2-targeted viruses. We have demonstrated that ALFc maintains picomolar activity (comparable to many of the previous leading monoclonal antibodies that received emergency use authorization) against all variants of SARS-CoV-2, and is highly effective in a hamster challenge model. Importantly, the ALFc has outstanding bioprocessing attributes, including stability at high concentrations and exceptional productivity using cGMP CHO production cell line. These attributes have led the U.S. Army to select ALFc to be advanced into clinical development over other ACE2 decoys; GMP materials for clinical trials and GLP tox studies are currently underway, and a Phase 1 clinical study is planned for 2H 2025. In this proposal, we build on the success of ALFc as an inhaled therapy to establish the efficacy of ALFc as a systemic immunoprophylaxis that can prevent severe pulmonary disease in vulnerable populations. Specifically, the ALFc currently in development possess wildtype IgG1-Fc. For sustained immunoprophylaxis lasting >6-9 months, it is essential to utilize Fc with enhanced affinity to FcRn, such as YTE, LS and DHS mutations. In this proposal, we will first produce and characterize ALFcYTE, ALFcLS and ALFcDHS(Aim 1). We will evaluate their activity against a panel of hACE2-targeting viruses, including emerging bat sarbecoviruses and merbecoviruses, using both pseudotyped alphavirus vectors in cell-lines (BSL-2) and infectious virus clones in well-differentiated cultures of human airway epithelial cells (BSL-3) (Aim 2). Finally, we evaluate the ability of ALFc to protect against infectious clones of SARS-CoV-2 and SHC014-CoV challenge in human ACE2 transgenic mice (Aim 3). Successful completion of these studies will likely advance an intervention for providing immunoprophylaxis against future SARS-CoV-2 variants as well as other hACE2-targeted coronaviruses with pandemic potential.", "keywords": [ "2019-nCoV", "ACE2", "Adult", "Affinity", "Allergic Reaction", "Alpha Virus", "Antibodies", "Binding", "Binding Proteins", "Biodistribution", "Biological Products", "COVID-19 pandemic", "COVID-19 treatment", "Cell Culture Techniques", "Cell Line", "Cells", "Chiroptera", "Circulation", "Clinical Research", "Clinical Trials", "Coronavirus", "Coronavirus Infections", "Cyclic GMP", "Data", "Development", "Dose", "Drug Kinetics", "Engineering", "Epithelial Cells", "Escape Mutant", "Evolution", "Excipients", "FDA Emergency Use Authorization", "Future", "Hamsters", "Human", "IgG1", "Immunocompromised Host", "Individual", "Infant", "Infection", "Inhalation", "Inhalation Therapy", "Intervention", "Length", "Link", "Literature", "Lung", "Lung Diseases", "Macaca", "Macaca mulatta", "Marketing", "Measures", "Merbecovirus", "Modeling", "Molecular Conformation", "Monoclonal Antibodies", "Mus", "Mutate", "Mutation", "Nebulizer", "Nose", "Parents", "Passive Immunization", "Phase", "Prevention", "Production", "Productivity", "Prophylactic treatment", "Proteins", "RNA vaccine", "Recording of previous events", "Research Personnel", "Risk", "SARS coronavirus", "SARS-CoV-2 infection", "SARS-CoV-2 spike protein", "SARS-CoV-2 variant", "Sarbecovirus", "Serum", "Temperature", "Testing", "Therapeutic", "Transgenic Mice", "Transgenic Organisms", "Vaccines", "Variant", "Viral", "Virus", "Virus Diseases", "Vulnerable Populations", "Work", "Zoonoses", "aerosolized", "airway epithelium", "bioprocess", "clinical development", "clinical material", "design", "extracellular", "flexibility", "immunoprophylaxis", "improved", "in vitro Model", "in vivo", "manufacture", "melting", "mutant", "neonatal Fc receptor", "pandemic coronavirus", "pandemic potential", "preservation", "prevent", "pulmonary", "receptor", "receptor binding", "success", "vector", "zoonotic coronavirus" ], "approved": true } }, { "type": "Grant", "id": "15728", "attributes": { "award_id": "2537245", "title": "Collaborative Research: Belmont Forum Collaborative Research: BIOrepositories build Adaptive and Resilient Capacity (BioARC)", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Unknown", "Intl Global Change Res & Coord" ], "program_reference_codes": [], "program_officials": [ { "id": 7800, "first_name": "Maria", "last_name": "Uhle", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-15", "end_date": null, "award_amount": 125998, "principal_investigator": { "id": 32778, "first_name": "John", "last_name": "Grieco", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 171, "ror": "https://ror.org/00mkhxb43", "name": "University of Notre Dame", "address": "", "city": "", "state": "IN", "zip": "", "country": "United States", "approved": true }, "abstract": "This award provides support to U.S. researchers participating in a project competitively selected by a 55-country initiative on global change research through the Belmont Forum. The Belmont Forum is a consortium of research funding organizations focused on support for transdisciplinary approaches to global environmental change challenges and opportunities. It aims to accelerate delivery of the international research most urgently needed to remove critical barriers to sustainability by aligning and mobilizing international resources. Each partner country provides funding for their researchers within a consortium to alleviate the need for funds to cross international borders. This approach facilitates effective leveraging of national resources to support excellent research on topics of global relevance best tackled through a multinational approach, recognizing that global challenges need global solutions. Working together in this Collaborative Research Action, the partner agencies have provided support to foster global transdisciplinary research teams of natural, health and social scientists and stakeholders from across the globe to improve understanding of climate, environment and health pathways to protect and promote health. The projects will provide crucial new understanding into the health implications arising from the impacts of climate change and variability on; 1) decision-science approaches to adaptation and implementation, 2) food, environment, and biological security and 3) risks to ecosystems and populations. This award provides support for the U.S. researchers to cooperate in consortia that consist of partners from at least three of the participating countries to increase our knowledge of the complex linkages and pathways between the climate, environment and health to help solve complex challenges that face societies. The BioARC project seeks to develop an interdisciplinary network of scientists, health professionals, and stakeholders to build the missing physical, human, and material infrastructure to stop pandemics at their source. These various forms of infrastructure will be centered on the development of multiple in-country biorepositories spread throughout The Americas, where pathogens with pandemic potential (e.g., Zika, Andes Virus) and neglected tropical diseases (e.g., Dengue, Chagas, and hookworm infection) have previously emerged and spread. This new infrastructure will provide the critical spatial, temporal, and taxonomic sampling and associated informatics necessary to understand the role of environmental drivers in host-pathogen dynamics, enabling a more proactive and predictive approach to pathogen emergence. This project directly addresses a critical challenge to pandemic preparedness. COVID-19 directly illustrated the high costs of pandemics to human wellbeing and the persistent gaps in our approach to preventing pathogen emergence. As humans and wildlife increasingly share space, opportunities for spillovers grow. Additionally, environmental stresses can cause wildlife to shed pathogens more readily as stress induced by things like habitat loss, heat exposure, or food scarcity decreases immune functionality that would typically keep pathogen shedding low. The project will focus on improving biorepository infrastructure including equipment and databases. The project team will develop training modules on museum science, fieldwork, molecular genetics, informatics, geospatial data analysis, science communication, and interdisciplinary network development. The project will develop best practices for biorepositories and relational databases for pathogens, interdisciplinary workflows for wildlife pathogen surveillance, communication across One Health disciplines, and strategies for biorepository decision-maker coordination. The goal of developing best practices is to enable the standardization of procedures for similar efforts locally and globally, and to form the foundation for an early-warning system for zoonotic diseases that will improve U.S. national security and build the U.S. workforce. The project will reduce costs of outbreak response by creating the capacity and data to establish baselines for wildlife pathogen dynamics, detecting deviations from these baselines, informing models, and enabling timely biosecurity decisions. The project will develop a robust, enduring system to safeguard human and animal populations from infectious diseases. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } } ], "meta": { "pagination": { "page": 2, "pages": 1405, "count": 14046 } } }