Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1405
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1405", "next": null, "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1404" }, "data": [ { "type": "Grant", "id": "15800", "attributes": { "award_id": "1F31AI191669-01", "title": "Uncovering the mechanisms and implications of BST2 antagonism by 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": 32891, "first_name": "MARY KATHERINE BRADFORD", "last_name": "PLIMACK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-07-01", "end_date": "2028-06-30", "award_amount": 49538, "principal_investigator": { "id": 32892, "first_name": "Haley", "last_name": "Aull", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2634, "ror": "", "name": "UNIVERSITY OF ROCHESTER", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "BST2/Tetherin is a key factor of the cellular intrinsic immune response that broadly restricts enveloped viruses. BST2 tethers nascent virions to the cell surface by embedding itself into cellular and viral membranes. Tethering not only limits viral release, but also facilitates adaptive immune recognition of the infecting virus. Tethered virions are opsonized by antibodies, which can be recognized by Fc receptors on both natural killer cells and macrophages, activating their ability to kill or phagocytose the infected cell. We have recently reported that SARS-CoV-2 is susceptible to BST2 restriction. However, the virus has evolved to use its Spike to downregulate BST2. Downregulation is achieved by an interaction between Spike and the extracellular domains of BST2, routing BST2 for lysosomal degradation in a Clathrin- and Ubiquitin-dependent manner. Remarkably, newly emerged variants of concern (VOC) have enhanced their ability to counteract BST2, suggesting that BST2 antagonism is a contributing factor to the host adaptation of SARS-CoV-2. Therefore, my long-term goal is to block the ability of SARS-CoV-2 to evade BST2 restriction. My overall objective is to understand the mechanism and implications of BST2 evasion by SARS-CoV-2. My central hypothesis is that mutations accumulated in the Spike of SARS-CoV-2 allow for more efficient counteraction of BST2, increasing virion release and reducing the susceptibility of SARS-CoV-2 to BST2-dependent antibody-mediated cellular responses. I will achieve my overall objective by exploring these two specific aims: (1) elucidate the mechanism of enhancement of BST2 antagonism across VOC, and (2) identify the driving pressures of BST2 antagonism. This work is significant as it will (1) fill the critical gap in knowledge of how SARS-CoV-2 evades BST2 restriction, and how VOC enhance this activity; (2) define the extent to which evasion of BST2 allows for evasion of antibody-mediated responses, and how this translates to vaccine efficacy; and (3) provide proof-of-concept for the design of antivirals to disable SARS-CoV- 2 antagonism of BST2 with the goal of both blocking viral replication and enhancing clearance of infected cells. The support provided by this F31 award will enhance my education by (1) facilitating my training in Surface Plasmon Resonance by Dr. Jermaine Jenkins and the URMC Structural Biology Core Facility (see letter of support), (2) allowing me to travel to the University of Wisconsin-Madison to gain hands-on training from my co- sponsor, Dr. David Evans (see co-sponsor statement), who developed assays to measure Fc receptor-mediated killing of infected cells, which we are proposing to use here, and (3) expanding my experience in scientific writing and communication as I publish my findings and present at both national and international conferences.", "keywords": [ "2019-nCoV", "Affinity", "Anti-viral Agents", "Antibodies", "Antibody-Dependent Enhancement", "Automobile Driving", "Award", "Binding", "Biological Assay", "COVID-19 susceptibility", "COVID-19 vaccine", "Cell surface", "Cells", "Clathrin", "Collaborations", "Communication", "Core Facility", "Coronavirus", "Defect", "Down-Regulation", "Education", "Extracellular Domain", "Fc Receptor", "Future", "Goals", "Immune", "Immune response", "Immunoprecipitation", "International", "Knowledge", "Letters", "Macrophage", "Maps", "Measures", "Mediating", "Membrane", "Mutation", "Natural Killer Cells", "Predisposition", "Process", "Proteins", "Publications", "Publishing", "Reporting", "Resistance", "Role", "Route", "SARS-CoV-2 B.1.1.529", "SARS-CoV-2 antibody", "Surface Plasmon Resonance", "Susceptibility Gene", "Testing", "Training", "Translating", "Travel", "Ubiquitin", "Universities", "Vaccine Design", "Viral", "Virion", "Virus", "Virus Replication", "Wisconsin", "Work", "Writing", "antagonist", "antibody-dependent cell cytotoxicity", "antibody-dependent cellular phagocytosis", "base", "design", "experience", "improved", "pressure", "response", "skills", "structural biology", "symposium", "vaccine efficacy", "variants of concern" ], "approved": true } }, { "type": "Grant", "id": "15801", "attributes": { "award_id": "1R21AI190246-01", "title": "Interrogating stress and viral shedding in a migratory bat model", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 32891, "first_name": "MARY KATHERINE BRADFORD", "last_name": "PLIMACK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-07-21", "end_date": "2027-06-30", "award_amount": 376932, "principal_investigator": { "id": 25386, "first_name": "Daniel", "last_name": "Becker", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2659, "ror": "", "name": "UNIVERSITY OF OKLAHOMA", "address": "", "city": "", "state": "OK", "zip": "", "country": "United States", "approved": true }, "abstract": "Bats harbor many zoonotic viruses, including both genera of coronaviruses (CoVs) pathogenic in humans (α- and β- CoVs). Limited evidence to-date suggests that periods of active infection in bats—and thus opportunities to transmit zoonotic viruses to humans—are driven by energetically demanding periods that modulate immune tolerance of infection and facilitate viral replication and shedding. However, such work has largely ignored immune mechanisms and has focused primarily on reproductive and nutritional stress. This project will combine field studies and in vitro analyses to test long-distance migration in bats as a driver of CoV infection and shedding. We will focus on Mexican free-tailed bats (Tadarida brasiliensis), a common and widespread migratory bat species in North America for which we and others have detected CoVs similar to HCoV-229E and that are susceptible to SARS-CoV-2. In Aim 1, we will sample T. brasiliensis at monthly intervals at our established study site in western Oklahoma, capturing energetically demanding periods of spring migration from Mexico, birth and lactation, and fall migration back to Mexico. We will characterize CoV diversity and infection status in saliva and fecal samples using RT-PCR followed by Sanger sequencing and will attempt to isolate naturally occuring bat CoVs. We will also quantify stress physiology through fecal cortisol and ratios of neutrophils to lymphocytes in blood, followed by generalized additive models to assess seasonality in physiological metrics and viral infection as well as to test how bat physiology relates to viral shedding. In Aim 2, we will collect lung and intestine from male and female T. brasiliensis bats and use our established protocols to develop new primary and immortalized cell lines, expanding the limited in vitro resources currently available for this bat species from an existing lung epithelial cell line. We will then test virus susceptibility and permissivity by infecting these new cell lines with HCoV 229E, SARS-CoV-2, and MERS-CoV; if isolation of natural bat CoVs is successful, we will also include infections with these viruses. Viral replication will be assessed by qRT-PCR, immunofluorescence microscopy, and TCID50 assays. In Aim 3, we will use our novel T. brasiliensis cell lines to run factorial viral and cortisol challenge experiments to mimic the stressors observed in the field and their impacts on virus replication (i.e., HCoV 229E, SARS-CoV-2, and MERS-CoV as well as any CoVs we isolate here). Viral and cortisol challenges will be followed by global gene expression analyses via RNA-Seq to discover the response of bat cells to field-relevant cortisol concentrations in the face of CoV infection. This project will thus characterize relationships between the physiological demands of migration and CoV infection in wild bats and in vitro systems, establishing a pipeline for studying how stressors affect bat-borne zoonoses.", "keywords": [ "2019-nCoV", "Affect", "Back", "Biological Assay", "Birth", "Blood", "COVID-19 detection", "COVID-19 susceptibility", "Cell Line", "Cell Physiology", "Cells", "Chiroptera", "Coronavirus", "Coronavirus Infections", "Couples", "Coupling", "Data", "Dideoxy Chain Termination DNA Sequencing", "Digestion", "Disease", "Enzyme-Linked Immunosorbent Assay", "Epithelial Cells", "Feces", "Female", "Gene Expression Profiling", "Genes", "Glucocorticoids", "Goals", "Hour", "Human", "Hydrocortisone", "Immune", "Immune Tolerance", "Immunocompetent", "Immunofluorescence Microscopy", "Immunosuppression", "In Vitro", "Indiana", "Infection", "Innate Immune System", "Intestines", "Lactation", "Lung", "Lymphocyte", "Mammals", "Measures", "Mediating", "Methods", "Mexican", "Mexico", "Middle East Respiratory Syndrome Coronavirus", "Modeling", "North America", "Nutritional", "Oklahoma", "Pathogenicity", "Peptide Hydrolases", "Physiological", "Physiological Processes", "Physiology", "Pilot Projects", "Predisposition", "Protocols documentation", "Quantitative Reverse Transcriptase PCR", "RNA", "Resources", "Reverse Transcriptase Polymerase Chain Reaction", "Running", "Saliva", "Sampling", "Seasonal Variations", "Seasons", "Site", "Stress", "System", "Tail", "Techniques", "Testing", "Time", "Trypsin", "Universities", "Vertebrates", "Viral", "Viral Genes", "Virulent", "Virus", "Virus Diseases", "Virus Replication", "Virus Shedding", "Washington", "Work", "Zoonoses", "bat-borne", "betacoronavirus", "cell immortalization", "cost", "experimental study", "falls", "field study", "gene network", "human coronavirus", "immunoregulation", "in vitro Model", "in vivo", "male", "medical schools", "migration", "neutrophil", "novel", "permissiveness", "reproductive", "response", "saliva sample", "sex", "stool sample", "stressor", "transcriptome", "transcriptome sequencing", "transmission process", "viral transmission", "virus testing" ], "approved": true } }, { "type": "Grant", "id": "15802", "attributes": { "award_id": "1R21AI183054-01A1", "title": "Formation of a Novel SARS-CoV-2 Nucleocapsid Dimer: Impacts on Viral and Cellular Processes", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 32891, "first_name": "MARY KATHERINE BRADFORD", "last_name": "PLIMACK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-07-08", "end_date": "2027-06-30", "award_amount": 438983, "principal_investigator": { "id": 23536, "first_name": "Emily A.", "last_name": "Bruce", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1131, "ror": "", "name": "UNIVERSITY OF VERMONT & ST AGRIC COLLEGE", "address": "", "city": "", "state": "VT", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1131, "ror": "", "name": "UNIVERSITY OF VERMONT & ST AGRIC COLLEGE", "address": "", "city": "", "state": "VT", "zip": "", "country": "United States", "approved": true }, "abstract": "While most SARS-CoV-2 research to date has focused on the biological consequences of mutations seen in the Spike (S) protein, the nucleocapsid protein (N) is also under selective pressure and an array of mutations within this protein have been documented in different Variants of Concern (VOCs). In this study, we identified three SARS-CoV-2 variants (Beta, Iota, and Delta) that encode different cysteine mutations, all introduced into the linker region of N. These mutations facilitate a highly stable N-N dimer mediated by the introduction of a cysteine and the formation of a di-sulfide bond. Beta, Iota, and Delta variants isolated and grown at BSL-3 all contained a novel cysteine residue in the linker region of N, which appear to be unique introductions amongst pandemic- causing Betacoronaviruses. Nucleoproteins encoding these cysteine mutations and transiently expressed in HEK-293T cells also form a dimer in the absence of other viral machinery. Removal of these cysteine mutations in the linker abolishes dimer formation. Notably, our biochemical studies also revealed this dimer is highly stable and can be visualized on standard non-reducing SDS-PAGE gels. Our proposal focuses on the G215C mutation, which quickly rose to dominance within the Delta lineages and mutations back to wildtype within transmission chains were quickly followed by a reversion to a cysteine at this position. Using reverse genetics, Drs Johnson and Menachery will construct a SARS-CoV-2 Delta virus that reverts the nucleocapsid cysteine back to the ancestral sequence to specifically evaluate N dimer impact on infection. This proposal aims to study the biological impact of stable N dimer formation during infection by characterizing viral growth kinetics (in vitro and in vivo) as well as the effect on viral fitness and transmission in the hamster model. Notably, a related virus (G215C in the WA1 background) showed substantially increased growth both in vitro and in vivo, suggesting that stable N dimer formation is important for viral replication. The stably dimerized form of N is highly enriched in virions (vs. the cellular environment) and we hypothesize it is increasing the efficiency of encapsidation and thus the stability of the viral RNA during transmission. As the cysteines we observe in the nucleocapsid linker lie near/on the N/NSP3 binding interface we will use proteomics to determine how the cellular and viral binding partners of the nucleoprotein change with/without this disulfide bond. Overall, the observation that mutations introducing a cysteine in the N linker have arisen multiple independent times and been maintained during human transmission, as well as our preliminary viral growth kinetics suggest that stable N dimer formation may drive positive selection and convey a growth advantage during SARS-CoV-2 infection and/or a selective benefit during animal-to-animal transmission.", "keywords": [ "2019-nCoV", "Affect", "Animals", "Back", "Binding", "Biochemical", "Biological", "Biological Assay", "Biology", "COVID-19 pandemic", "Cell Physiology", "Cells", "Code", "Collaborations", "Coronavirus", "Cysteine", "Data", "Dimerization", "Elements", "Environment", "Epithelial Cells", "Excision", "Gel", "Genome", "Genomics", "Growth", "Hamsters", "Human", "Immune Evasion", "Immune response", "In Vitro", "Individual", "Infection", "Inflammation", "Interferons", "Kinetics", "Mass Spectrum Analysis", "Mediating", "Middle East Respiratory Syndrome", "Modeling", "Molecular Weight", "Mutation", "Nucleocapsid", "Nucleocapsid Proteins", "Nucleoproteins", "Organoids", "Pathogenesis", "Play", "Population", "Positioning Attribute", "Process", "Production", "Proteins", "Proteomics", "Public Health", "RNA", "RNA Binding", "RNA Stability", "RNA-Directed RNA Polymerase", "Research", "Role", "SARS-CoV-2 B.1.617.2", "SARS-CoV-2 infection", "SARS-CoV-2 variant", "SH2D3C gene", "Severe Acute Respiratory Syndrome", "Shapes", "Site", "System", "Testing", "Vaccines", "Variant", "Viral", "Viral Genome", "Viral Pathogenesis", "Viral Proteins", "Virion", "Virus", "Virus Replication", "Visualization", "airway epithelium", "betacoronavirus", "clinical predictors", "dimer", "disulfide bond", "fitness", "flexibility", "genomic RNA", "improved", "in vivo", "insight", "loss of function", "migration", "monomer", "mutant", "novel", "novel coronavirus", "pandemic disease", "pressure", "reverse genetics", "structural biology", "transmission process", "variants of concern", "viral RNA", "viral fitness", "viral transmission", "virology", "virus host interaction" ], "approved": true } }, { "type": "Grant", "id": "15803", "attributes": { "award_id": "1I01HX003797-01A3", "title": "Evaluating Veterans' Reproductive Healthcare Access, Quality and Outcomes in a Changing Landscape (EVOLVE)", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2025-07-01", "end_date": "2029-06-30", "award_amount": null, "principal_investigator": { "id": 32893, "first_name": "Lisa Susanne", "last_name": "Callegari", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32894, "first_name": "Deirdre A", "last_name": "Quinn", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2660, "ror": "", "name": "VA PUGET SOUND HEALTHCARE SYSTEM", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "Background: Recent years have witnessed unprecedented changes in the reproductive healthcare landscape in the US, including heightened awareness of reproductive health inequities following the 2020 nationwide racial justice reckoning, barriers to access resulting from the COVID-19 pandemic, and the proliferation of state abortion restrictions and bans following the 2022 Dobbs v Jackson Supreme Court decision. Today, access to high-quality, equitable contraceptive care has never been more vital for Veterans, who face elevated risks of poor outcomes from unintended pregnancy due to high rates of health comorbidities and psychosocial risks. The Examining Contraceptive Use and Unmet Need in Veterans (ECUUN) survey fielded in 2014-16 by study team members demonstrated high rates of unintended pregnancy and gaps in VA contraceptive access and quality, with significant disparities among Black and Latinx Veterans. While the ECUUN study helped inform VA’s reproductive health policies to date, updated data are urgently needed to capture VA’s progress in addressing disparities over time as well as its ability to meet Veterans’ needs in today’s shifted landscape. Significance: This study will generate timely quantitative and qualitative data necessary for VA as a learning health system to address gaps in access and quality and to adapt its policies and programming to meet Veterans’ changing needs. In addition, this study focuses on contraceptive counseling experiences in marginalized Veterans, for whom this care may be fraught due to the US history of reproductive oppression such as forced sterilization and policies to punish or limit reproduction in racial minority and low-income people. Findings will enable VA to respond to new White House and congressional directives related to women’s health that call for research to advance reproductive healthcare access and reduce disparities in care. Innovation & Impact: This proposal is innovative in its timeliness, use of prior data to draw novel comparisons over time, deployment of new state-of-the-art person-centered measures not yet fielded in VA such as the National Quality Forum (NQF)-endorsed Person-Centered Contraceptive Counseling (PCCC) measure, and collection of data to capture experiences of VA’s new policy to provide abortion care in select cases. Specific Aims: Aim 1: To use quantitative survey data to examine changes over time since ECUUN in contraceptive use, unintended pregnancy, and abortion, including differences by Veteran characteristics (e.g., race/ethnicity, geography). Aim 2: To use quantitative survey data to test for current disparities in novel person-centered measures (e.g., PCCC) by Veteran characteristics and characteristics of their health care. Aim 3: To contextualize Aim 1 & 2 findings, including disparities in experiences of contraceptive care and unintended pregnancy/abortion, by conducting qualitative interviews with Veterans. Methodology: This is a sequential explanatory mixed methods study beginning with a national survey of 3,600 pregnancy-capable reproductive-age Veterans who used VA primary or gynecology care in the past year. Qualitative interviews will then be conducted among Veteran survey respondents, purposively sampling at-risk subgroups (Black, Latinx, rural, residence in abortion-restrictive state) whose survey responses indicate gaps in care quality or equity. Quantitative data will inform qualitative sampling and data collection, and quantitative and qualitative data will be integrated using mixed methods analytic techniques including joint displays. Next Steps/Implementation: Next steps will include conducting a stakeholder engagement meeting with Veterans, women’s health providers, and operational partners from the Offices of Women’s Health, Health Equity, and Rural Health to share key research findings, develop strategic goals, and prioritize interventions to address disparities in contraceptive access and quality. Ultimately, this study has the potential to enhance VA’s ability to be a national leader in delivering high-quality and person-centered reproductive healthcare and to inform efforts to advance quality and equity in reproductive healthcare both within and beyond the VA.", "keywords": [ "Address", "Awareness", "Black race", "COVID-19 pandemic", "Caring", "Characteristics", "Clinic", "Clinical", "Coercion", "Collaborations", "Congresses", "Constitution", "Contraceptive Agents", "Contraceptive Usage", "Contraceptive methods", "Counseling", "Data", "Data Collection", "Development", "Disparity", "Equity", "Ethnic Origin", "Exclusion", "Female", "Geography", "Goals", "Gynecology", "Health", "Health Care", "Health Personnel", "Health Policy", "Health system", "Individual", "Intention", "Intervention", "Interview", "Investments", "Involuntary Sterilization", "Joints", "Judgment", "Justice", "Latina", "Latinx", "Lead", "Learning", "Low Income Population", "Low income", "Measures", "Medical", "Medical Records", "Mental Health", "Methodology", "Methods", "Mission", "Movement", "Outcome", "Personal Satisfaction", "Persons", "Policies", "Populations at Risk", "Pregnancy", "Proliferating", "Provider", "Punishment", "Quality of Care", "Race", "Recording of previous events", "Reproduction", "Reproductive Health", "Reproductive History", "Research", "Respondent", "Risk", "Rural", "Rural Health", "Sampling", "Services", "Subgroup", "Supreme Court Decisions", "Surveys", "Techniques", "Testing", "Time", "Trust", "United States Department of Veterans Affairs", "Update", "Veterans", "Voice", "Women's Health", "abortion", "access disparities", "analytical method", "comorbidity", "disparity reduction", "experience", "field survey", "gaps in access", "gender minority group", "health care availability", "health care disparity", "health care settings", "health equity", "health inequalities", "innovation", "marginalization", "marginalized population", "medical vulnerability", "meetings", "member", "novel", "patient oriented", "people of color", "person centered", "preference", "pregnancy related death", "prevent", "primary care provider", "psychosocial", "racial disparity", "racial minority", "reproductive", "reproductive age", "residence", "response", "rural area", "rurality", "sample collection", "sexual minority group", "sexual trauma", "social", "unintended pregnancy" ], "approved": true } }, { "type": "Grant", "id": "15804", "attributes": { "award_id": "1R01AI187899-01A1", "title": "Optimizing lipid RVn monophosphate prodrugs to maximize RVn-triphosphate delivery", "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": "2025-07-18", "end_date": "2029-06-30", "award_amount": 3082513, "principal_investigator": { "id": 32895, "first_name": "Aaron F.", "last_name": "Carlin", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2637, "ror": "", "name": "UNIVERSITY OF CALIFORNIA, SAN DIEGO", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Emerging RNA viruses, especially respiratory viruses, are among the leading threats to global health. With few treatments currently available, there is an urgent and ongoing need for the development of safe, effective oral antivirals. The objective of this application is to optimize an innovative lipid prodrug delivery strategy for remdesivir nucleoside monophosphate (RVn-MP), and additional broad-spectrum nucleoside antivirals, to achieve 1) excellent oral bioavailability, 2) efficient intracellular activation across tissue types, and 3) bypass of liver metabolism to enhance tissue delivery. The central hypothesis is that specific modifications to the lipid prodrug scaffold can improve in vivo antiviral efficacy by enhancing prodrug metabolism to the active metabolite and augmenting tissue delivery. The rationale for this project is that a better understanding of how lipid prodrug modifications increase antiviral activity will allow for the rational design and development of novel broad- spectrum oral antivirals for the treatment of clinically important RNA viruses. Strategy: Aim 1 will identify the mechanisms that determine prodrug antiviral potency in vitro to maximize antiviral activity. Quantitation of lipid RVn-MP prodrugs and their metabolites in cell culture using mass spectrometry will determine how scaffold modifications alter uptake, metabolism, and antiviral activity. Genetic knockout studies will identify the specific phospholipase C (PLC) enzyme/s that are necessary for lipid RVn-MP prodrug metabolism across cell types. Finally, PLC enzyme kinetic studies will identify scaffold modifications that maximize metabolism and antiviral activity in vitro. These data will inform lipid prodrug scaffold design that optimizes lipid RVn-MP potency. Aim 2 will determine how lipid prodrug modifications control distribution to maximize tissue delivery. First-pass removal of oral drugs by the liver is a common problem in drug development. We will evaluate how oral lipid nucleoside prodrugs can partition into chylomicrons, move through lymphatics to the thoracic duct, and thereby avoid first-pass liver metabolism while increasing lung delivery. Structure-activity relationship studies using a library of lipid RVn prodrugs will identify scaffold modifications that increase intestinal lymphatic trafficking and improve serum pharmacokinetics and tissue distribution. Scaffolds that maximize in vitro antiviral activity (Aim 1) and in vivo lung delivery (Aim 2) will be selected to rationally design new lipid RVn- MP prodrugs and novel lipid prodrugs containing nucleosides with broad spectrum activity against RNA viruses. New compounds will be evaluated for increased metabolism and antiviral activity in vitro, tissue delivery in vivo, and efficacy against pathogenic coronaviruses and dengue in mice. Collectively, this proposal will optimize the antiviral efficacy of oral lipid RVn-MP prodrugs for the treatment of many clinically important RNA viruses. Additionally, a better understanding of how to maximize the efficacy of lipid nucleoside prodrug design may be the key to unlocking a whole new generation of broad-spectrum antivirals.", "keywords": [ "2019-nCoV", "Affect", "Anti-viral Agents", "Biological Availability", "Bypass", "COVID-19 treatment", "Cell Culture Techniques", "Chylomicrons", "Clinical", "Clinical Treatment", "Coronavirus", "Data", "Dengue", "Dengue Virus", "Development", "Drug Kinetics", "Drug or chemical Tissue Distribution", "Ebola", "Enzyme Kinetics", "Enzymes", "Esters", "Excision", "Filovirus", "Flavivirus", "GS-441524", "Generations", "Genetic", "Glycerol", "In Vitro", "Intestines", "Knock-out", "Libraries", "Lipids", "Liver", "Lung", "Lymphatic", "Lysophospholipids", "Marburgvirus", "Mass Spectrum Analysis", "Metabolic", "Metabolism", "Methods", "Mission", "Modification", "Mus", "National Institute of Allergy and Infectious Disease", "Nipah", "Nucleosides", "Oral", "Oral Administration", "Paramyxovirus", "Pathogenicity", "Pharmaceutical Preparations", "Phospholipase C", "Plasma", "Positioning Attribute", "Prodrugs", "Public Health", "Publishing", "RNA Virus Infections", "RNA Viruses", "RNA-Directed RNA Polymerase", "Series", "Serum", "Site", "Small Intestines", "Structure-Activity Relationship", "Synthesis Chemistry", "Therapeutic", "Thoracic Duct", "Tissues", "Viral", "Viral Physiology", "Virus", "Virus Replication", "absorption", "analog", "anti-viral efficacy", "cell type", "design", "drug development", "esterase", "global health", "improved", "in vitro activity", "in vivo", "innovation", "lipophilicity", "liver metabolism", "mouse model", "novel", "nucleoside monophosphate", "pandemic potential", "preclinical efficacy", "rational design", "remdesivir", "respiratory virus", "scaffold", "targeted delivery", "trafficking", "tripolyphosphate", "uptake" ], "approved": true } }, { "type": "Grant", "id": "15805", "attributes": { "award_id": "1K01DA062904-01", "title": "Clinician cannabis use-related preconceptions perpetuating low quality of prenatal care for women who use cannabis during pregnancy", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Drug Abuse (NIDA)" ], "program_reference_codes": [], "program_officials": [ { "id": 32896, "first_name": "SARAH", "last_name": "VIDAL", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-07-15", "end_date": "2030-06-30", "award_amount": 196236, "principal_investigator": { "id": 32897, "first_name": "Rachel Carmen", "last_name": "Ceasar", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2622, "ror": "", "name": "UNIVERSITY OF SOUTHERN CALIFORNIA", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Cannabis is the most used illicit substance during pregnancy. Rates of self-medicating with cannabis escalated during the COVID-19 pandemic. The scientific objective of this proposal is to investigate the mechanisms contributing to preconceptions about those who use cannabis, especially during pregnancy. The central hypothesis is that preconceptions about those who use cannabis result in negative interactions between patients and clinicians that reduce the quality of healthcare and result in poor outcomes. This innovative project will be the first to: (a) leverage natural language processing/artificial intelligence (NLP/AI) techniques to investigate preconceptions about cannabis use in clinical notes, and (b) investigate associations between cannabis use and prenatal care quality. Research aims will: (Aim 1) Investigate preconceptions about those who use cannabis during pregnancy using a mixed methods approach that integrates NLP/AI and qualitative interviews; (Aim 2) Investigate associations between cannabis use and prenatal care quality among different population groups, such as differences in socioeconomic status and education levels; and (Aim 3) Develop, adapt, and test the feasibility and usability of a clinician training on quality health care practices for those who use cannabis during pregnancy using a multistage modified Delphi process, survey, and qualitative focus groups. This research is complemented by a training plan that builds upon Dr. Rachel Carmen Ceasar’s background in mixed qualitative-quantitative methods and substance use research. The training plan includes using NLP/AI approaches, advanced survey methods in reproductive epidemiology, and implementation science. Together, this research and training will prepare Dr. Ceasar to advance as an independent investigator conducting research on health and substance use among those who are pregnant across the lifespan. The proposed project will improve clinicians’ care of those who use cannabis during pregnancy, providing evidence to inform the development of interventions designed to reduce cannabis-use-related notions in prenatal care.", "keywords": [ "Adverse effects", "American College of Obstetricians and Gynecologists", "Artificial Intelligence", "Belief", "COVID-19 pandemic", "California", "Cannabis", "Caring", "Child Welfare", "Clinical", "Clinical Treatment", "Consensus", "Cross-Sectional Studies", "Data", "Detection", "Education", "Educational Status", "Family", "Focus Groups", "Fright", "Future", "Goals", "Guidelines", "Gynecologic", "Health", "Health Benefit", "Health Care", "Income", "Infant", "Interview", "Knowledge", "Language", "Legal", "Link", "Los Angeles", "Medical", "Medical center", "Mentored Research Scientist Development Award", "Mentors", "Methods", "Modeling", "Moods", "Mothers", "Natural Language Processing", "Nausea", "Outcome", "Output", "Pain", "Patient Outcomes Assessments", "Patients", "Persons", "Policies", "Policy Maker", "Population", "Population Group", "Pregnancy", "Pregnancy Outcome", "Pregnant Women", "Prenatal care", "Prevalence", "Process", "Quality of Care", "Questionnaires", "Recommendation", "Reporting", "Research", "Research Personnel", "Rice", "Risk", "Socioeconomic Status", "Supervision", "Survey Methodology", "Surveys", "Techniques", "Testing", "Time", "Training", "Woman", "authority", "cannabis cessation", "comparative", "efficacy evaluation", "evidence base", "experience", "feasibility testing", "follow-up", "health care delivery", "health care quality", "implementation science", "improved", "indexing", "innovation", "large language model", "life span", "low socioeconomic status", "marijuana use", "marijuana use in pregnancy", "neurodevelopment", "open source", "preconception", "prenatal", "provider behavior", "reproductive epidemiology", "substance use", "therapy design", "therapy development", "usability" ], "approved": true } } ], "meta": { "pagination": { "page": 1405, "pages": 1405, "count": 14046 } } }