Grant List
Represents Grant table in the DB
GET /v1/grants?sort=-id
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-id", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1405&sort=-id", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=2&sort=-id", "prev": null }, "data": [ { "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 } }, { "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": "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": "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": "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": "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": "15799", "attributes": { "award_id": "1R43CA298267-01A1", "title": "Ultra-precision diagnostics for ALK+ non-small cell lung cancer", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Cancer Institute (NCI)" ], "program_reference_codes": [], "program_officials": [ { "id": 32888, "first_name": "SWAMY KRISHNA", "last_name": "TRIPURANI", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-07-09", "end_date": "2026-06-30", "award_amount": 399153, "principal_investigator": { "id": 32889, "first_name": "David Randall", "last_name": "Armant", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32890, "first_name": "Rodrigo C", "last_name": "Fernandez-Valdivia", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2658, "ror": "", "name": "ALELOPHARMA INC.", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true }, "abstract": "Background & Significance: Identifying ALK-positive lesions, which are highly responsive to treatment with Crizotinib or Alectinib, is a high-priority for managing patients with ALK+ Non-Small Cell Lung Cancer (NSCLC). A blood-based companion diagnostic (liquid biopsy) could monitor NSCLC patients post-treatment for tumor recurrence without tissue re-biopsy, and also identify non-symptomatic ALK+ individuals for earlier, more effective treatment with ALK kinase inhibitors. Expansion of this approach to other major oncogenic mutations has potential as a non-invasive cancer screening tool that would be transformative for healthcare. Objective & Innovation: AleloPharma Inc. is achieving solutions for personalized precision medicine using AleloMAX, an innnovative high-dimensional molecular detection system that allows ultra-specific detection of target nucleic acids with an impressive 1-absolute copy per reacting assay limit-of-detection (LOD) that effectively eliminates both false positives and false negatives. We aim to offer clinicians a cutting-edge diagnostic capable of accurately detecting ALK translocations among cell-free RNA in the blood plasma of affected patients. Approach: A proof-of-principle study, supported by preliminary LOD data obtained with synthetic ALK constructs, is proposed to develop a liquid biopsy test to detect ALK translocation variants in a kit for use in clinical labs. • Specific Aim 1: Develop an ultra-specific and ultra-sensitive molecular detection platform for EML4-ALK gene fusion translocations in ALK+ NSCLC. We will probe EML4-ALK fusion RNAs using synthetic, in vitro-transcribed mRNAs encompassing the distinct EML4-ALK oncogenic variants. • Specific Aim 2: Demonstrate AleloMAX-ALK’s superior resolution power in ultra-specific molecular probing and limit-of-detection (LOD) analysis in a clinical proof-of-principle study. The EML4-ALK diagnostic platform will be tested using plasma- and/or blood-derived nucleic acid samples obtained from ALK+ NSCLC patients, ALK- NSCLC patients, and healthy control volunteers. Team & Commercialization: Led by a distinguished team with a track record of groundbreaking research in molecular pharmacology, oncology and cellular biology, we are uniquely positioned to tackle this challenge. Our clear roadmap includes patenting all IP and aspires to launch a diagnostic that will have significant clinical utility. Feasibility & Impact: The assay is expected to detect low levels of EML4-ALK mutations in blood of individuals with ALK+ NSCLC. AleloMAX demonstrated diagnostic superiority in prior studies of the NSCLC biomarker POGLUT-1, SARS-CoV-2 and RSV with impressive results. Assay parameters established in this project will be developed as a kit for use in a Phase II study to establish its clinical utility as a companion diagnostic for NSCLC. Successful development of an ALK+ cancer diagnostic will be expanded to include assays for RET, ROS1 and other onco-mutations with additional AleloMAX liquid biopsy assays to monitor a broader panel of cancers. Conclusion: Combining innovation and tangible clinical benefit, our initiative represents a transformative shift in early detection and management of cancer that will positively impact patient survival.", "keywords": [ "2019-nCoV", "ALK gene", "Acceleration", "Address", "Affect", "Aftercare", "Algorithms", "Archives", "Award", "Biological Assay", "Biopsy", "Blood", "Businesses", "COVID-19 diagnosis", "Cancer Detection", "Cancer Diagnostics", "Cancer Patient", "Cells", "Cellular biology", "Chemistry", "Chromosomal translocation", "Clinical", "DNA Sequence Alteration", "Data", "Detection", "Development", "Diagnosis", "Diagnostic", "Diagnostic tests", "Disease", "Early Diagnosis", "Evaluation", "Event", "Fluorescent in Situ Hybridization", "Future", "Gene Amplification", "Gene Fusion", "Genetic Transcription", "Health Care", "Image", "In Vitro", "Individual", "Industry", "Legal patent", "Lesion", "Malignant Neoplasms", "Malignant neoplasm of lung", "Marketing", "Methods", "Molecular", "Molecular Genetics", "Molecular Probes", "Monitor", "Mutation", "Neoplasms", "Non-Small-Cell Lung Carcinoma", "Nucleic Acids", "Oncogenes", "Oncogenic", "Oncology", "Patient Monitoring", "Patients", "Performance", "Pharmacology", "Phase", "Plasma", "Positioning Attribute", "Probability", "Procedures", "Process", "Prognosis", "Protein Tyrosine Kinase", "RNA", "ROS1 gene", "Reaction", "Recurrent tumor", "Research", "Resolution", "Sampling", "Screening for cancer", "Screening procedure", "Sensitivity and Specificity", "Series", "Signal Transduction", "Specificity", "Techniques", "Technology", "Testing", "Therapeutic", "Therapeutic Intervention", "Time", "Tissues", "Transcript", "Tube", "Tyrosine Kinase Inhibitor", "Variant", "Vision", "Work", "biobank", "cancer biomarkers", "cancer diagnosis", "chromosome fusion", "cohort", "commercialization", "companion diagnostics", "comparative", "crizotinib", "detection assay", "detection limit", "detection platform", "diagnostic platform", "diagnostic technologies", "diagnostic tool", "diagnostic value", "early screening", "effective intervention", "effective therapy", "genetic diagnostics", "high dimensionality", "improved", "inhibitor", "innovation", "kinase inhibitor", "liquid biopsy", "molecular diagnostics", "next generation", "next generation sequencing", "novel", "overexpression", "patient screening", "personalized diagnostics", "phase 2 study", "precision medicine", "screening", "sensor technology", "success", "tumor", "validation studies", "volunteer" ], "approved": true } }, { "type": "Grant", "id": "15798", "attributes": { "award_id": "1DP2AI192737-01", "title": "Decoding multidrug-resistant pathogen dynamics for clinically-relevant wastewater surveillance", "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": 32875, "first_name": "INKA I", "last_name": "SASTALLA", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-07-23", "end_date": "2030-06-30", "award_amount": 534000, "principal_investigator": { "id": 32887, "first_name": "Medini K", "last_name": "Annavajhala", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2657, "ror": "", "name": "CHILDREN'S HOSP OF PHILADELPHIA", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "Multidrug-resistant bacteria (MDRB) contribute increasingly to morbidity, mortality, and healthcare costs. Extended-spectrum beta-lactam- and carbapenem-resistant Enterobacterales (ESBL-E and CRE) are MDRB of particular concern due to their demonstrated ability to evolve into highly transmissible clones and acquire and spread antibiotic resistance determinants. Traditional epidemiological surveillance typically focuses on outbreaks of MDRB causing clinical infections, underestimating the burden of these pathogens within hospital systems. Broader efforts that account for asymptomatic carriage and environmental and community reservoirs would be ideal to track and mitigate the spread of MDRB. Wastewater surveillance has proven an effective tool for public health pathogen monitoring, as shown with SARS-CoV-2, but has not been established in clinical settings. This proposal will develop new systems to leverage wastewater for clinically applicable, proactive, and readily deployable MDRB monitoring. In Aim 1, we will establish standardized longitudinal surveillance strategies to inform infection control responses. We will use long-read metagenomics and novel bioinformatic approaches to rapidly identify significant changes in relative or absolute abundance of ESBL-E or CRE compared to site-specific baselines. We will also establish methods to translate wastewater testing data into interpretable “action thresholds” for use by hospital and clinical teams. In Aim 2, we will identify factors enabling the emergence of novel ESBL-E and CRE genotypes in the wastewater environment. Wastewater sampling can identify novel resistant genotypes before detection of clinical infections. We will further develop our novel Metapore-C technique to link bacterial hosts with resistance gene-harboring mobile elements and will use this approach to identify environmental factors such as wastewater antibiotic levels and plumbing design associated with acquisition of resistance. Lastly, in Aim 3 we will devise wastewater testing methodologies suited to resource-limited clinical settings. Given the costs and infrastructure needed for comprehensive clinical surveillance, wastewater testing is better poised to aid in mitigation of MDRB under resource constraints. Yet, current wastewater surveillance approaches are often impractical in such settings. Our strategies for reducing per-sample costs and the analytical burden of wastewater data interpretation, as piloted at a pediatric hospital in Gaborone, Botswana, will serve as a proof-of-concept for wastewater MDRB testing in diverse contexts. Overall, this project will significantly broaden the ability of wastewater surveillance to inform hospital and clinical care efforts, while establishing best practices for global surveillance of antimicrobial resistance in hospital wastewater.", "keywords": [ "2019-nCoV", "Address", "Antibiotic Resistance", "Antibiotics", "Antimicrobial Resistance", "Bacterial Infections", "Bioinformatics", "Biological Testing", "Botswana", "COVID-19 pandemic", "Childhood", "Clinical", "Communities", "Complement", "Data", "Data Analyses", "Detection", "Development", "Disease Outbreaks", "Elements", "Enabling Factors", "Environment", "Environmental Risk Factor", "Epidemiologic Monitoring", "Epidemiology", "Genetic Materials", "Genomics", "Genotype", "Goals", "Health Care Costs", "Health Care Systems", "Horizontal Gene Transfer", "Hospitals", "Infection", "Infection Control", "Infection prevention", "Infrastructure", "Link", "Metagenomics", "Methodology", "Methods", "Mobile Genetic Elements", "Molecular", "Monitor", "Morbidity - disease rate", "Multi-Drug Resistance", "Outcome", "Patients", "Pediatric Hospitals", "Plasmids", "Plumbing", "Population", "Postdoctoral Fellow", "Prevalence", "Protocols documentation", "Public Health", "Research", "Resistance", "Resource-limited setting", "Resources", "Sampling", "Site", "Standardization", "System", "Techniques", "Testing", "Therapeutic", "Thinking", "Translating", "Treatment Failure", "United States", "Work", "beta-Lactams", "bioinformatics pipeline", "carbapenem resistant Enterobacterales", "clinical application", "clinical care", "clinical sequencing", "clinically relevant", "combat", "cost", "cost effective", "design", "experience", "health care settings", "hospital care", "improved", "innovation", "low and middle-income countries", "microbiome", "microbiota", "microorganism", "mortality", "multi-drug resistant bacteria", "multi-drug resistant pathogen", "novel", "pathogen", "resistance gene", "resistance mechanism", "response", "surveillance strategy", "tool", "wastewater sampling", "wastewater surveillance", "wastewater testing" ], "approved": true } }, { "type": "Grant", "id": "15797", "attributes": { "award_id": "1R01HL176849-01A1", "title": "Pathogenic mechanisms of chronic lung sequelae following respiratory viral infection", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Heart Lung and Blood Institute (NHLBI)" ], "program_reference_codes": [], "program_officials": [ { "id": 32514, "first_name": "EMMANUEL FRANCK", "last_name": "MONGODIN", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-10", "end_date": "2029-05-31", "award_amount": 754729, "principal_investigator": { "id": 32886, "first_name": "John F", "last_name": "Alcorn", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32525, "first_name": "Lianghui", "last_name": "Zhang", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 848, "ror": "", "name": "UNIVERSITY OF PITTSBURGH AT PITTSBURGH", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "The COVID-19 pandemic has brought the world’s attention on respiratory viral infections. It is not a question of if another respiratory viral pandemic will arise, but rather when. The diversity of viral pathogens presents a tremendous challenge for designing virus targeted preventions and therapeutics. However, respiratory viruses cause similar lung injury that drives morbidity and mortality. A focus on host mediated lung injury pathways in this context is warranted, as there is potential for therapeutic interventions that would be effective across a range of respiratory viral infections. The COVID-19 pandemic has drawn attention to a poorly characterized phenotype of persistent lung inflammation that lasts well beyond clearance of live virus. Long-COVID and long-Flu are clinical diagnoses that lack an understanding of the molecular underpinnings of disease. In this application, we focus on understanding the mechanism by which respiratory viral infection causes lasting tissue damage covering antigen persistence, presentation, and a positive feedback inflammatory cell network. We propose that the persistent presence of viral antigen in pulmonary endothelial cells is a major driver for the prolonged activation of CD8+ T cells, consequently leading to chronic pulmonary sequelae, through reinforced interaction of CD8+ TRM cells and pro-inflammatory macrophages. This hypothesis will be tested in two Aims: 1) we will investigate the contribution of persistent activation of CD8+ T cells by pulmonary endothelial cells to the development of chronic pulmonary sequelae, and 2) we will interrogate the T cell and macrophage inflammatory axis in persistent inflammation during recovery from respiratory viral infection. To examine these pathways, we will employ the SARS-CoV-2 and influenza virus mouse models, and we will confirm findings using tissue from human patient transbronchial biopsies. Discovery of causative host inflammatory pathways that are critical to post-viral lung sequelae would provide pre-clinical evidence to support clinical trials. If pathogenic mechanisms are indeed similar between multiple respiratory viruses, then host-directed therapeutics would potentially have a tremendous impact. Currently, there are no specific therapies indicated for the treatment of post-viral lung inflammation.", "keywords": [ "2019-nCoV", "Acute", "Antibodies", "Antigen Presentation", "Antigen-Presenting Cells", "Antigens", "Attention", "Automobile Driving", "Biopsy", "Biopsy Specimen", "CD8-Positive T-Lymphocytes", "CD8B1 gene", "COVID-19 pandemic", "Cells", "Chronic", "Clinical Trials", "Coronavirus Infections", "Critical Pathways", "Data", "Development", "Disease", "Economic Burden", "Endothelial Cells", "Endothelium", "Epidemic", "Exudate", "Feedback", "Fibrosis", "Frustration", "Functional disorder", "Goals", "Human", "IFNGR1 gene", "Immune", "In Vitro", "Infection", "Inflammation", "Inflammatory", "Influenza", "Influenza A Virus H1N1 Subtype", "Interferon Type II", "Intervention", "Knock-out", "Long COVID", "Lung", "Lymphocyte", "Lymphoid", "MHC Class I Genes", "Macrophage", "Mediating", "Metabolism", "Molecular", "Morbidity - disease rate", "Mus", "Myelogenous", "Pathogenesis", "Pathogenicity", "Pathologic", "Pathway interactions", "Patients", "Phenotype", "Population", "Post-Acute Sequelae of SARS-CoV-2 Infection", "Prevention", "Production", "Proteins", "Public Health", "Pulmonary Inflammation", "Recovery", "Resolution", "Role", "SARS-CoV-2 infection", "Signal Transduction", "Source", "T-Lymphocyte", "T-cell inflamed", "Testing", "Therapeutic", "Therapeutic Intervention", "Tissues", "Upper Respiratory Infections", "Viral", "Viral Antigens", "Viral Respiratory Tract Infection", "Virus", "Virus Diseases", "Work", "beta-2 Microglobulin", "clinical diagnosis", "coronavirus pandemic", "cytokine", "design", "effector T cell", "experience", "flu", "human tissue", "influenza infection", "influenzavirus", "lung injury", "lung microvascular endothelial cells", "lung repair", "mortality", "mouse model", "neutralizing antibody", "novel", "pathogenic virus", "pharmacologic", "polarized cell", "pre-clinical", "pulmonary", "pulmonary vascular cells", "repaired", "respiratory", "respiratory virus", "restoration", "single-cell RNA sequencing", "socioeconomics", "spatial transcriptomics", "tissue resident memory T cell", "viral pandemic" ], "approved": true } }, { "type": "Grant", "id": "15796", "attributes": { "award_id": "1R44NS145848-01", "title": "Development of Tissue Engineered Tregs as a Treatment for Acute Ischemic Stroke", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Neurological Disorders and Stroke (NINDS)" ], "program_reference_codes": [], "program_officials": [ { "id": 32884, "first_name": "FLOY ANNETTE", "last_name": "GILCHRIST", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-15", "end_date": "2027-07-31", "award_amount": 1150417, "principal_investigator": { "id": 32885, "first_name": "Payam", "last_name": "Zarin", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2656, "ror": "", "name": "GENTIBIO, INC.", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "In the U.S., nearly 800,000 individuals experience a stroke each year, predominantly ischemic strokes. The economic burden of stroke is staggering, with projected stroke-related medical costs in the U.S. expected to surpass $94 billion by 2035. This underscores the urgent need for effective therapies to address this significant public health challenge. While the potential of regulatory T cells (Tregs) in promoting stroke recovery has been recognized, translating this promise into clinical success has been hampered by several obstacles. Traditional Treg therapies face challenges in manufacturing, phenotypic instability, and a lack of tissue specificity. This proposal focuses on the development of allogeneic engineered tissue Tregs (EngTregs) as a novel off-the-shelf therapeutic approach for stroke. Overexpression of ST2, the receptor for the alarmin IL-33, enhances the ability of EngTregs to: (i) sense and respond to tissue damage (ST2-expressing EngTregs efficiently migrate to sites of inflammation and injury); (ii) suppress excessive inflammation (EngTregs exert potent anti-inflammatory effects through multiple mechanisms, including direct suppression of immune cells and modulation of the inflammatory environment); and (iii) actively participate in tissue repair (EngTregs produce growth factors and interact with other cells to promote tissue regeneration). Overexpression of FOXP3 ensures a stable and suppressive Treg phenotype, crucial for long-term therapeutic efficacy. A chemically induced signaling complex (CISC) enables tunable IL-2 signaling, promoting Treg survival and function while facilitating scalable manufacturing. These innovations culminate in a first-in-class allogeneic tissue EngTreg product with advantages in manufacturing scalability, cost-effectiveness, and therapeutic potential compared to conventional Treg therapies. Preliminary studies demonstrate the ability of allogeneic EngTregs to accumulate in the injured brain and improve motor skills, sensory function, learning, and memory following ischemic injury induced in the transient middle cerebral artery occlusion (tMCAO) mouse model of stroke. This proposal outlines three aims to further advance the preclinical development of EngTregs for stroke: Aim 1: Evaluate the therapeutic efficacy of EngTregs in two preclinical stroke models (permanent middle cerebral artery occlusion and photothrombosis) in both adult and aged mice, assessing a comprehensive range of functional and histological outcomes. Aim 2: Characterize the mechanism of action and define a comprehensive in vitro profile of the human EngTreg drug product, including assessment of cytokine sequestration, T cell suppression, macrophage polarization, and transcriptomic analysis. Aim 3: Assess the immunotoxicity and immunogenicity of human EngTregs to ensure clinical safety, including evaluation of cytokine release syndrome and allo-immunogenicity. Successful completion of these aims will provide critical preclinical data supporting the clinical translation of EngTregs as a novel and promising therapeutic strategy for stroke, addressing a significant unmet medical need.", "keywords": [ "AREG gene", "Acute", "Address", "Adhesives", "Adult", "Age", "Allogenic", "Antiinflammatory Effect", "Area", "Autologous", "Biological Assay", "Blood flow", "Brain Injuries", "C57BL/6 Mouse", "CCR5 gene", "CCR8 gene", "Cell Physiology", "Cell Survival", "Cell Therapy", "Cells", "Cessation of life", "Characteristics", "Chemicals", "Clinical", "Clinical Data", "Cognitive", "Complex", "Development", "Economic Burden", "Engraftment", "Ensure", "Evaluation", "FOXP3 gene", "Face", "Female", "Flow Cytometry", "Growth Factor", "Guidelines", "Health Care Systems", "High Prevalence", "Histologic", "Homing", "Human Engineering", "IL2RA gene", "Immune Cell Suppression", "In Vitro", "Individual", "Infarction", "Inflammation", "Inflammatory", "Injury", "Interleukin-13", "Interleukin-2", "Ischemic Stroke", "Learning", "Macrophage", "Mediating", "Medical", "Medical Care Costs", "Memory", "Middle Cerebral Artery Occlusion", "Mixed Lymphocyte Culture Test", "Modeling", "Motor Skills", "Mus", "Outcome", "Outcome Measure", "Patient-Focused Outcomes", "Patients", "Performance", "Persons", "Pharmaceutical Preparations", "Phase", "Phenotype", "Preclinical data", "Process", "Public Health", "Receptors Tumor Necrosis Factor Type II", "Recovery of Function", "Regulatory T-Lymphocyte", "Reperfusion Therapy", "Research", "Risk", "Safety", "Sensory", "Signal Induction", "Signal Transduction", "Sirolimus", "Site", "Specificity", "Stroke", "T cell therapy", "T-Lymphocyte", "TNFRSF1B gene", "Testing", "Therapeutic", "Tissue Engineering", "Tissues", "Toxic effect", "Translating", "Treatment Efficacy", "Upregulation", "Work", "aged", "angiogenesis", "axon injury", "blood-brain barrier permeabilization", "brain repair", "clinical translation", "cost", "cost effectiveness", "cytokine", "cytokine release syndrome", "disability", "disease heterogeneity", "effective therapy", "experience", "foot", "human tissue", "immunogenicity", "immunotoxicity", "improved", "inflammatory milieu", "inflammatory modulation", "innovation", "ischemic injury", "male", "manufacture", "manufacturing process", "migration", "morris water maze", "mortality", "mouse model", "neurogenesis", "novel", "object recognition", "old mice", "osteopontin", "overexpression", "patient subsets", "post stroke", "pre-clinical", "preclinical development", "preclinical evaluation", "programs", "public health relevance", "receptor", "repaired", "stroke model", "stroke recovery", "stro" ], "approved": true } } ], "meta": { "pagination": { "page": 1, "pages": 1405, "count": 14046 } } }