Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=2&sort=-end_date
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-end_date", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1392&sort=-end_date", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=3&sort=-end_date", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-end_date" }, "data": [ { "type": "Grant", "id": "14974", "attributes": { "award_id": "5R35HL167143-02", "title": "The epigenetic regulation of inflammation in tissue repair and vascular disease", "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": 24365, "first_name": "Cheryl", "last_name": "McDonald", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-07-01", "end_date": "2030-06-30", "award_amount": 1053460, "principal_investigator": { "id": 21384, "first_name": "Katherine Ann", "last_name": "Gallagher", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 770, "ror": "", "name": "UNIVERSITY OF MICHIGAN AT ANN ARBOR", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true }, "abstract": "The overarching theme for our research program over the past 10 years has been to better understand the etiology and pathogenesis of chronic inflammation in tissue repair processes and vascular disease, with a particular interest in how epigenetics influences the innate immune response and shapes pathologic and homeostatic processes. Our laboratory has contributed seminal studies related to 1) epigenetic regulation of myeloid cells that alter inflammation in abdominal aortic aneurysms (AAA), 2) regulation of macrophage phenotypes by chromatin modifying enzymes (CMEs) during tissue repair, 3) prostaglandin regulation of macrophage plasticity in the setting of tissue repair, 4) chemokines and other signaling pathways driving monocyte recruitment to injured tissue and tissue macrophage phenotypes, 5) epigenetic alterations that impact macrophage function in COVID-19 infection, 6) metabolomic and other biomarker studies in tissue regeneration and cardiovascular disease, 7) role of epigenetic regulation of macrophages following recovery from sepsis. Our work has utilized animal models to carry out mechanistic studies and patient-derived cells and tissues to confirm relevant pathways, identify therapeutic targets and characterize novel biomarkers. Based on our previously published observations and novel preliminary data, our laboratory is broadly focused in 4 main areas. The first serves as a continuation and expansion of HL156274 grant (currently in year 2) to complete and advance therapeutically relevant studies of JMJD3 and other critical CMEs in AAA development. The second goal will serve as renewal of HL137919 and allow us explore JAK/STAT signaling in tissue macrophages and blood monocytes and the downstream regulation of CMEs and subsequent inflammation in a variety of conditions (tissue regeneration, AAAs and post-sepsis recovery). The third goal will be to explore the interactions between structural cells (SMCs, keratinocytes, fibroblasts) and myeloid cells in the setting of tissue regeneration and AAA development. The fourth will be an expansion into the area of peripheral atherosclerosis where we will explore epigenetic regulation of macrophage phenotype/function in the setting of peripheral atherosclerotic disease (PAD). This emerging investigator award (EIA) mechanism will allow us to extend our studies in each of these areas and will allow for mechanistic understanding of the role of epigenetic regulation of macrophage phenotypes in the pathogenesis of a breadth of cardiovascular disease processes including tissue regeneration, aneurysm formation and peripheral atherosclerosis. It will also allow our laboratory to complete proof-of-concept and validation studies needed in both animals and humans to advance new therapies to the clinics for treatment of cardiovascular diseases.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "11717", "attributes": { "award_id": "1R35HL167143-01", "title": "The epigenetic regulation of inflammation in tissue repair and vascular disease", "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": 24365, "first_name": "Cheryl", "last_name": "McDonald", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-07-01", "end_date": "2030-06-30", "award_amount": 1101440, "principal_investigator": { "id": 21384, "first_name": "Katherine Ann", "last_name": "Gallagher", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 770, "ror": "", "name": "UNIVERSITY OF MICHIGAN AT ANN ARBOR", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true }, "abstract": "The overarching theme for our research program over the past 10 years has been to better understand the etiology and pathogenesis of chronic inflammation in tissue repair processes and vascular disease, with a particular interest in how epigenetics influences the innate immune response and shapes pathologic and homeostatic processes. Our laboratory has contributed seminal studies related to 1) epigenetic regulation of myeloid cells that alter inflammation in abdominal aortic aneurysms (AAA), 2) regulation of macrophage phenotypes by chromatin modifying enzymes (CMEs) during tissue repair, 3) prostaglandin regulation of macrophage plasticity in the setting of tissue repair, 4) chemokines and other signaling pathways driving monocyte recruitment to injured tissue and tissue macrophage phenotypes, 5) epigenetic alterations that impact macrophage function in COVID-19 infection, 6) metabolomic and other biomarker studies in tissue regeneration and cardiovascular disease, 7) role of epigenetic regulation of macrophages following recovery from sepsis. Our work has utilized animal models to carry out mechanistic studies and patient-derived cells and tissues to confirm relevant pathways, identify therapeutic targets and characterize novel biomarkers. Based on our previously published observations and novel preliminary data, our laboratory is broadly focused in 4 main areas. The first serves as a continuation and expansion of HL156274 grant (currently in year 2) to complete and advance therapeutically relevant studies of JMJD3 and other critical CMEs in AAA development. The second goal will serve as renewal of HL137919 and allow us explore JAK/STAT signaling in tissue macrophages and blood monocytes and the downstream regulation of CMEs and subsequent inflammation in a variety of conditions (tissue regeneration, AAAs and post-sepsis recovery). The third goal will be to explore the interactions between structural cells (SMCs, keratinocytes, fibroblasts) and myeloid cells in the setting of tissue regeneration and AAA development. The fourth will be an expansion into the area of peripheral atherosclerosis where we will explore epigenetic regulation of macrophage phenotype/function in the setting of peripheral atherosclerotic disease (PAD). This emerging investigator award (EIA) mechanism will allow us to extend our studies in each of these areas and will allow for mechanistic understanding of the role of epigenetic regulation of macrophage phenotypes in the pathogenesis of a breadth of cardiovascular disease processes including tissue regeneration, aneurysm formation and peripheral atherosclerosis. It will also allow our laboratory to complete proof-of-concept and validation studies needed in both animals and humans to advance new therapies to the clinics for treatment of cardiovascular diseases.", "keywords": [ "Abdominal Aortic Aneurysm", "Aneurysm", "Animal Model", "Animals", "Area", "Atherosclerosis", "Automobile Driving", "Award", "Biological Markers", "Cardiovascular Diseases", "Cells", "Chromatin", "Chronic", "Clinic", "Data", "Development", "Enzymes", "Epigenetic Process", "Etiology", "Fibroblasts", "Goals", "Grant", "Human", "Inflammation", "Innate Immune Response", "Laboratories", "Myeloid Cells", "Pathogenesis", "Pathologic", "Pathway interactions", "Patients", "Peripheral", "Phenotype", "Process", "Prostaglandins", "Publishing", "Recovery", "Regulation", "Research", "Research Personnel", "Role", "SARS-CoV-2 infection", "Seminal", "Sepsis", "Shapes", "Signal Pathway", "Signal Transduction", "Smooth Muscle Myocytes", "Therapeutic", "Tissues", "Vascular Diseases", "Work", "chemokine", "coronavirus disease", "epigenetic regulation", "immunoregulation", "injured", "interest", "keratinocyte", "macrophage", "metabolomics", "monocyte", "novel", "novel marker", "novel therapeutics", "programs", "recruit", "therapeutic target", "tissue injury", "tissue regeneration", "tissue repair", "validation studies" ], "approved": true } }, { "type": "Grant", "id": "11419", "attributes": { "award_id": "1UM1TR004407-01", "title": "Scripps Clinical and Translational Science Hub", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Center for Advancing Translational Sciences (NCATS)" ], "program_reference_codes": [], "program_officials": [ { "id": 21379, "first_name": "SOJU", "last_name": "Chang", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-05-01", "end_date": "2030-04-30", "award_amount": 6029792, "principal_investigator": { "id": 23339, "first_name": "Eric Jeffrey", "last_name": "Topol", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 745, "ror": "", "name": "SCRIPPS RESEARCH INSTITUTE, THE", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 745, "ror": "", "name": "SCRIPPS RESEARCH INSTITUTE, THE", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "/ ABSTRACT The Scripps Research Translational Institute (SRTI) is the foundation for the Scripps hub and is dedicated to accelerating science that will improve human health. SRTI’s emphasis on genomics, digital medicine, and informatics/analytics fosters a multi-dimensional understanding of individualized human health. The Scripps hub has previously included the Scripps Research Institute (SR) and Scripps Health (SH) as principal partners, including Rady Children’s Institute of Genomic Medicine (RCIGM) for genomic medicine initiatives and California Institute for Medical Research (Calibr) for drug repurposing / discovery. In the new CTSA cycle, our partners have expanded to include San Diego State University (SDSU), enabling us to combine forces in computer science, artificial intelligence, biosensors, and diversity inclusion and equity initatives. SRTI’s expertise in genomics was highlighted during the pandemic. We became one of the country’s most productive sequencing centers for SARS-CoV-2 by rapidly forming the “SEARCH” alliance to process samples with the San Diego County Department of Health, UCSD, Sharp Health, California Department of Public Health, Helix, and our partners RCIGM and SH. Digital medicine has been one of SRTI’s core strengths, having pioneered the first remote, site-less digital clinical trial and now expanding this methodology to address many other medical conditions such as health during pregnancy and sleep disorders. Our Digital Trials Center launched the Digital Engagement & Tracking for Early Control and Treatment Scripps (DETECT) study, and in a matter of weeks our team was able to accurately predict the likelihood of Covid with SARS-CoV-2 using passively collected resting heart rate data from wristband sensors and later to identify a physiologic signature that correlates with Long Covid (Post-Acute Sequelae or SARS-CoV-2 Infection). The Scripps hub will innovate clinical and translational science to improve human health across the lifespan and diverse racial, ethnic, geographic and socioeconomic communities. The hub will provide a nurturing environment for education, training, and career development with a focus on individualized health domains of genomics, digital medicine, and biomedical informatics, to empower tomorrow’s diverse workforce.", "keywords": [ "2019-nCoV", "Acceleration", "Address", "Area", "Artificial Intelligence", "Awareness", "Biosensor", "California", "Child", "Clinical Research", "Clinical Sciences", "Clinical Trials", "Collaborations", "Communities", "Country", "County", "Data", "Data Aggregation", "Data Set", "Dedications", "Democracy", "Diagnostic", "Dimensions", "Dissemination and Implementation", "Diverse Workforce", "Drug Screening", "Ecosystem", "Education", "Elements", "Ethics", "Ethnic Origin", "Fostering", "Foundations", "Genomic medicine", "Genomics", "Geography", "Goals", "Health", "Healthcare", "Heart Rate", "Human", "Human Resources", "Industry Collaboration", "Informatics", "Institute of Medicine (U.S.)", "Institution", "Intervention", "Longevity", "Medical", "Medical Research", "Methodology", "Modeling", "Outcome", "Patients", "Physiological", "Population", "Post-Acute Sequelae of SARS-CoV-2 Infection", "Preventive", "Process", "Productivity", "Program Development", "Public Health", "Public Health Informatics", "Race", "Research", "Research Institute", "Research Project Grants", "Resource Informatics", "Resources", "Rest", "SARS-CoV-2 infection", "Sampling", "Science", "Services", "Site", "Sleep Disorders", "Structure", "Techniques", "Time", "Training", "Translational Research", "Universities", "Vision", "Voice", "biomedical informatics", "career development", "community engaged research", "community engagement", "computer science", "computerized data processing", "cost effective", "data standards", "digital", "digital medicine", "digital models", "digital twin", "diversity and inclusion", "drug repurposing", "educational atmosphere", "empowerment", "equity diversity and inclusion", "ethnic diversity", "health data", "health equity", "health inequalities", "improved", "individualized medicine", "innovation", "interoperability", "multimodal data", "multimodality", "pandemic disease", "pregnancy disorder", "programs", "public health emergency", "racial diversity", "real time model", "response", "secondary analysis", "sensor", "socioeconomics", "tool", "translational approach" ], "approved": true } }, { "type": "Grant", "id": "11203", "attributes": { "award_id": "1UG1HD112092-01", "title": "Maternal Fetal Medicine Units Network: University of California, San Francisco", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)" ], "program_reference_codes": [], "program_officials": [ { "id": 22555, "first_name": "Nahida Abdo", "last_name": "Chakhtoura", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-04-01", "end_date": "2030-03-31", "award_amount": 355300, "principal_investigator": { "id": 27221, "first_name": "MARY E", "last_name": "NORTON", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 768, "ror": "https://ror.org/043mz5j54", "name": "University of California, San Francisco", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Significant disparities in maternal and infant mortality and morbidity exist in the U.S, and the MFMU Network aims to reduce the rates of preterm birth, fetal growth abnormalities, newborn morbidity, and maternal complications of pregnancy. Novel strategies, including new therapies and technologies, innovative study designs and interventions, attention to implementation science, inclusion of adequately diverse study participants into clinical trials, and input from the stakeholders impacted by health disparities are needed to improve outcomes for pregnant and lactating people. Although California accounts for nearly one eighth of annual U.S. births, the MFMU Network lacks a West Coast site. The University of California, San Francisco (UCSF) has a racially and ethnically diverse patient population, including many individuals with differing gender identities. The inclusion of historically marginalized communities, including segments of the population that are highly represented in California, will ensure the MFMU Network study results are generalizable, and will promote health equity for all persons. UCSF is a pioneer in innovative research techniques, such as genomics and metagenomics, as well as clinical research methods, including community partnership and implementation science. In addition, UCSF has a robust research infrastructure that has supported numerous translational investigations including epigenetics and infection studies, metagenomic sequencing in pregnant patients with obstetric complications, studies of environmental contaminants such as wildfire smoke on reproductive outcomes, and placental biology, including the impact of COVID-19 and COVID vaccines. UCSF has an extensive network of affiliated practices and referring hospitals that provide care for diverse patient populations with a myriad of pregnancy- related complications and together with its affiliate, Zuckerberg San Francisco General Hospital, performs nearly 4000 deliveries per year in mostly high-risk patients. Therefore, to support the mission of the MFMU Network, we will 1) Enroll a large and uniquely diverse, west coast participant population; 2) Contribute multidisciplinary expertise of UCSF investigators to high priority areas of public health that impact pregnant people and/or their infants, such as the COVID pandemic, the opioid crisis, and the impacts of climate change; and 3) Leverage our affiliation with the MFMU Network to develop a diverse group of young academic investigators. UCSF will bring a host of novel and innovative opportunities, including clinical populations and unique technological and research approaches that will strengthen the work of the MFMU Network.", "keywords": [ "Address", "Area", "Attention", "Basic Science", "Birth", "Black race", "COVID-19 impact", "COVID-19 pandemic", "California", "Caring", "Clinic", "Clinical", "Clinical Research", "Clinical Services", "Clinical Trials", "Collection", "Comprehensive Health Care", "Conscious", "DNA", "Diabetes Mellitus", "Education", "Endocrinology", "Enrollment", "Ensure", "Environment", "Environmental Impact", "Environmental Pollutants", "Epigenetic Process", "Ethnic Origin", "Ethnic group", "Fetal Growth", "Gender Identity", "General Hospitals", "Genetic", "Genomics", "Goals", "Health system", "Heart Diseases", "Hospitals", "Housing", "Hypertension", "Individual", "Infant", "Infection", "Infrastructure", "Intervention", "Investigation", "Lactation", "Maternal Mortality", "Maternal complication", "Maternal-Fetal Medicine Units Network", "Maternal-fetal medicine", "Metagenomics", "Methodology", "Mission", "Molecular", "Morbidity - disease rate", "Multi-Institutional Clinical Trial", "Multicenter Trials", "Neurology", "Newborn Infant", "Outcome", "Outpatients", "Participant", "Patients", "Perinatal", "Perinatal Care", "Persons", "Pharmacogenomics", "Placental Biology", "Plasma", "Population", "Pregnancy Complications", "Pregnancy Outcome", "Premature Birth", "Prenatal Diagnosis", "Public Health", "Race", "Recruitment Activity", "Reproductive Endocrinology", "Research", "Research Design", "Research Infrastructure", "Research Methodology", "Research Personnel", "Research Technics", "Resources", "Safety", "San Francisco", "Site", "Smoke", "Technology", "Tissues", "Training Programs", "Translational Research", "Underrepresented Minority", "Universities", "Vaccines", "Wildfire", "Work", "climate change", "climate impact", "clinical care", "community partnership", "coronavirus disease", "ethnic diversity", "experience", "fetal", "health disparity", "health equity promotion", "high risk", "implementation science", "improved", "improved outcome", "in utero", "infant morbidity/mortality", "innovation", "marginalized community", "medical specialties", "metagenomic sequencing", "microbial", "multidisciplinary", "new technology", "novel", "novel strategies", "novel therapeutics", "obstetric care", "obstetrical complication", "opioid epidemic", "patient oriented", "patient population", "perinatal medicine", "perinatal mental health", "personalized approach", "precision medicine", "pregnancy heal" ], "approved": true } }, { "type": "Grant", "id": "15599", "attributes": { "award_id": "1R01CA301643-01", "title": "Role of respiratory viral infections and inflammation in promoting metastatic outgrowth in the lung", "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": 21648, "first_name": "Elizabeth Lee", "last_name": "Read-Connole", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-03-01", "end_date": "2030-02-28", "award_amount": 672011, "principal_investigator": { "id": 32096, "first_name": "James V", "last_name": "Degregori", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32097, "first_name": "Mercedes", "last_name": "Rincon", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 784, "ror": "https://ror.org/02hh7en24", "name": "University of Colorado Denver", "address": "", "city": "", "state": "CO", "zip": "", "country": "United States", "approved": true }, "abstract": "The leading cause of breast cancer deaths is metastasis. Metastatic relapse can occur months to years after the initial diagnosis and treatment of the primary tumor. Cancer cells can disseminate from the primary tumor into different tissues including lungs and remain in a dormant state for years to decades. Awakening of these dormant disseminated cancer cells (DCC) leads to metastasis. Finding factors that trigger the awakening of dormant DCC and developing strategies to reduce the risk of awakening is therefore an unmet need. While it is known that inflammation is a key contributing factor to the awakening of dormant DCC, no studies have investigated whether inflammation triggered by viral respiratory infections (a very common infection worldwide) in the lung can promote the expansion of DCC and lead to the development of metastases. Our recent studies using a mouse model of breast cancer DCC dormancy in the lung have revealed a dramatic increase in DCC awakening and expansion in the lungs following influenza virus infection. Our data support the hypothesis that respiratory viral infections can promote DCC awakening and expansion through two phases: first, through IL-6 dependent DCC awakening and expansion, and second, CD4 T-cell mediated protection from elimination (in part by CD8 cells). We further show that infection with a mouse-adapted SARS-CoV-2 promotes a similar awakening and expansion of DCC in mice. Finally, epidemiological studies reveal how prior infection with SARS-CoV-2 infection increases metastatic progression in lungs and cancer- related deaths for cancer survivors. We propose to determine mechanisms by which acute respiratory viral infections induce the awakening of dormant DCC leading to metastatic disease, whether and how such infections can prime DCC for activation by subsequent exposures, and how CD4 and CD8 cells differentially control the persistence of expanded DCC during influenza virus infection. Impact: Proposed studies to understand how different pulmonary viral infections alter DCC dormancy and host immune responses, to determine the consequences for progression to metastatic disease, and to explore underlying mechanisms, should yield valuable and actionable insight into the key cell types and molecular mediators, informing early detection and prevention strategies for at-risk individuals.", "keywords": [ "2019-nCoV", "Acute", "Affect", "B-Lymphocytes", "Biological Markers", "Breast", "Breast Cancer Model", "Bronchus-Associated Lymphoid Tissue", "CD4 Positive T Lymphocytes", "CD8-Positive T-Lymphocytes", "COVID-19", "COVID-19 pandemic", "Cancer Patient", "Cancer Survivor", "Cells", "Cessation of life", "Data", "Development", "Diagnosis", "Disease", "Early Diagnosis", "Epidemic", "Epithelial Cells", "Genetic Transcription", "IL6 gene", "Immune", "Immune response", "Individual", "Infection", "Inflammation", "Inflammatory", "Influenza", "Interleukin-6", "Intervention", "Link", "Lung", "Lung infections", "Lymphocytic choriomeningitis virus", "Lymphoid Tissue", "Maintenance", "Malignant Breast Neoplasm", "Malignant Neoplasms", "Malignant neoplasm of lung", "Mediating", "Mediator", "Mesenchymal", "Metastatic Neoplasm to the Lung", "Metastatic/Recurrent", "Modeling", "Molecular", "Mus", "Neoplasm Metastasis", "Pathway interactions", "Persons", "Phase", "Phenotype", "Prevalence", "Prevention strategy", "Primary Neoplasm", "Proliferating", "Relapse", "Research", "Respiratory Tract Infections", "Risk", "Risk Reduction", "Role", "SARS-CoV-2 infection", "Seasons", "Signal Pathway", "Signal Transduction", "Source", "Testing", "Tissues", "Upregulation", "Viral", "Viral Respiratory Tract Infection", "Virus", "Virus Diseases", "cancer cell", "cell type", "cigarette smoking", "cytokine", "epidemiology study", "experience", "influenza infection", "influenzavirus", "insight", "mouse model", "pandemic disease", "prevent", "programs", "progression risk", "respiratory", "response", "risk mitigation", "seasonal influenza" ], "approved": true } }, { "type": "Grant", "id": "15600", "attributes": { "award_id": "1K23AI187708-01", "title": "Active and passive humoral immunity to enteric adenovirus infection in Bangladeshi children", "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": 7031, "first_name": "RUTH HUAB", "last_name": "Florese", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-03-01", "end_date": "2030-02-28", "award_amount": 192260, "principal_investigator": { "id": 32098, "first_name": "Jennifer Marie", "last_name": "Hendrick", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 908, "ror": "https://ror.org/0153tk833", "name": "University of Virginia", "address": "", "city": "", "state": "VA", "zip": "", "country": "United States", "approved": true }, "abstract": "Candidate: I am an Assistant Professor at the University of Virginia (UVA) in the Division of Infectious Disease and International Health and a KL2- Funded Scholar in the Integrated Translational Health Research Institute of Virginia (iTHRIV) Scholars Program. I have pursued research in host pathogen immune interactions with Dr. William Petri for the past 6 years. Beginning initially with enteric pathogens and shifting to SARS-CoV-2 during the pandemic, I will now return to my work in diarrheal disease utilizing my background in viral immunology through study of adenovirus (AdV) 40/41 infection, a major cause of childhood diarrheal illness in low- and middle- income countries (LMIC). Career Development Plan/Career Goals & Objectives: My goal is to become an independent translational investigator. I will do so by furthering my knowledge base in the design of clinical trials, host pathogen immune interactions, viral immunology and data analysis. I will utilize my advisory committee who are not only successfully funded researchers but have a proven track record for mentoring young physician scientists. Research Plan: Characterize the systemic and mucosal immune response to AdV 40/41 infection in children in Bangladesh and determine the efficacy breast milk antibodies in providing passive immunity. Aim 1 (PASSIVE IMMUNITY): (1A) Describe the antibody repertoire to AdV 40/41 in the breast milk of mothers of Bangladeshi children using a novel protein microarray and (1B) determine their association with infection in the first 2 years of life. Plan: Determine maternal breast milk antibody breadth and magnitude, and test for its association to infant infection. Aim 2 (ACTIVE IMMUNITY): Characterize the antibody responses to AdV 40/41 infection in Bangladeshi children and test for their association with subsequent infection utilizing longitudinal (2A) serum and (2B) stool samples. Plan: Describe mucosal and systemic antibody scope and magnitude and test for association with protection from subsequent infection. Mentor/Co-Mentor(s), and Collaborator(s): The primary mentor of this K23, Dr. Petri, has a 30-year record of NIH Funding and has mentored 10 prior K awardees, 6 of whom have already made the K to R transition. My mentors include experts in immunology, virology, childhood diarrheal disease and statistics. Environment and Institutional Commitment to the Candidate: The intellectual environment at UVA is robust. I have a strong commitment from my Department and Division assuring 90% protected research time regardless of the outcome of this K23 proposal, and support of my continued mentorship under Dr. Petri at UVA.", "keywords": [ "2 year old", "2019-nCoV", "5 year old", "Active immunity", "Address", "Adenovirus Protein", "Adenoviruses", "Advisory Committees", "Affect", "Antibodies", "Antibody Repertoire", "Antibody Response", "Antigens", "Bangladesh", "Bangladeshi", "Biometry", "Birth", "Cause of Death", "Child", "Childhood", "Clinical Trials Design", "Cohort Studies", "Communicable Diseases", "Data", "Data Analyses", "Development", "Development Plans", "Diarrhea", "Disease", "Enteral", "Environment", "Faculty", "Feces", "Fellowship", "Filtration", "Funding", "Goals", "Growth", "Health", "Human Milk", "Humoral Immunities", "Immune", "Immune Targeting", "Immune response", "Immunity", "Immunology", "Infant", "Infection", "Institution", "Internal Medicine", "International", "Intervention", "Knowledge", "Life", "Longitudinal cohort", "Maternal antibody", "Measures", "Mentors", "Mentorship", "Morbidity - disease rate", "Mothers", "Mucosal Immune Responses", "Mucous Membrane", "Outcome", "Passive Immunity", "Passive Transfer of Immunity", "Physicians", "Plasma", "Polymerase Chain Reaction", "Population", "Population Attributable Risks", "Protein Microchips", "Publishing", "Recurrent disease", "Reproducibility", "Research", "Research Institute", "Research Personnel", "Residencies", "Sampling", "Scholars Program", "Scientist", "Serum", "Testing", "Time", "Translational Research", "United States National Institutes of Health", "Universities", "Vaccination", "Viral", "Virginia", "Virus", "Work", "biobank", "career", "career development", "cohort", "cost effective", "design", "diarrheal disease", "efficacy evaluation", "enteric adenovirus infection", "enteric infection", "enteric pathogen", "infant infection", "innovation", "insight", "knowledge base", "low and middle-income countries", "low income country", "maternal vaccination", "member", "molecular diagnostics", "mortality", "neurodevelopment", "novel", "pandemic disease", "pathogen", "prevent", "professor", "recurrent infection", "response", "statistics", "stool sample", "translational health science", "translational scientist", "vaccination strategy", "vaccine development", "virology" ], "approved": true } }, { "type": "Grant", "id": "15598", "attributes": { "award_id": "1R01ES037151-01", "title": "Multi-component INTERLUNG intervention to protect lung health in Nepal", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Environmental Health Sciences (NIEHS)" ], "program_reference_codes": [], "program_officials": [ { "id": 11803, "first_name": "Claudia L", "last_name": "Thompson", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-03-19", "end_date": "2030-02-28", "award_amount": 893525, "principal_investigator": { "id": 9093, "first_name": "William", "last_name": "Checkley", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 265, "ror": "https://ror.org/03czfpz43", "name": "Emory University", "address": "", "city": "", "state": "GA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 344, "ror": "https://ror.org/00za53h95", "name": "Johns Hopkins University", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "Chronic respiratory diseases (CRDs) remain the third leading cause of death worldwide and their incidence is increasing. In 2019, it was estimated that 455 million people worldwide live with a CRD such as asthma, COPD, and chronic bronchitis. CRDs are responsible for 4 million deaths and 103.5 million disability-adjusted life years lost each year. The development and severity of CRDs is attributed to both environmental exposures and infectious causes. Individuals who live in densely populated cities in low- and middle-income countries (LMICs) are disproportionately affected by high levels of ambient particulate matter, indoor exposure to allergens, dust and tobacco smoke, and a high incidence of viral and bacterial infections. Therefore, to have a meaningful impact on the incidence and severity of CRDs, and prevent further lung function decline, a multi- component evidence-based intervention targeting multiple risk factors is needed. We seek to test the implementation and effectiveness of a tailored multi-component evidence-based intervention following a community health worker (CHW)-driven chronic care delivery model to protect lung health over a 40-month period using a Type I hybrid implementation-effectiveness randomized controlled trial in Bhaktapur, Nepal. The multi-component intervention will consist of: reducing environmental risk factors by targeting tobacco smoking through CHW-delivered messaging and education on smoking prevention and smoking cessation, and targeting indoor and ambient air pollution exposures by providing households with HEPA-indoor air purifiers and vacuum cleaners and encourage masking outdoors with N95 respirators when e-notified about days with high ambient air pollution; reducing infectious risks through an CHW-led vaccine campaign for annual influenza, COVID and pneumococcal vaccine in all eligible participants and household members; encouraging use of surgical masks in indoor public spaces during the peak winter season or at home when there are sick household contacts; and, improving physiologic health by encouraging physical activity through CHW- monitored pedometer goals. Aligned with the Consolidated Framework for Implementation Research, we will first conduct human-centered design workshops with community members and healthcare practitioners to tailor the multi-component intervention. We will then screen and identify 800 index participants aged ≥ 9 years (with a pre-bronchodilator FEV1/FVC Z-score ≤ 10th percentile and chronic cough or wheeze (i.e., at-risk participants). We will enroll index participants and household members and assign half of the households to the adapted intervention. Controls will be asked to continue usual care practices. We will evaluate the effect of the intervention on pre-bronchodilator FEV1 Z-score (primary outcome), respiratory symptoms, and evaluate implementation outcomes. We seek to facilitate scale-up of a multi-component intervention that responds to the real-world implementation context to protect lung health in Nepal and other LMICs.", "keywords": [ "Adherence", "Adopted", "Adoption", "Affect", "Air Pollution", "Allergens", "Asthma", "Bacterial Infections", "Behavior", "Bronchodilator Agents", "COVID-19 vaccine", "Cause of Death", "Censuses", "Cessation of life", "Chronic", "Chronic Bronchitis", "Chronic Care", "Chronic Obstructive Pulmonary Disease", "Cities", "Communities", "Community Health Aides", "Consolidated Framework for Implementation Research", "Coughing", "Data", "Development", "Dust", "Education", "Educational workshop", "Effectiveness", "Enrollment", "Environmental Exposure", "Environmental Risk Factor", "Evidence based intervention", "Exposure to", "Future", "Goals", "Government Officials", "Hand", "Health", "Health Care", "Health system", "Home", "Household", "Household Air Pollution", "Hygiene", "Incidence", "Individual", "Indoor Air Pollution", "Inhalation", "Intervention", "Lateral", "Lower respiratory tract structure", "Masks", "Modeling", "Monitor", "N95 mask", "Nepal", "Notification", "Participant", "Particulate Matter", "Perception", "Persons", "Physical activity", "Physiological", "Pneumococcal vaccine", "Policies", "Process", "Pulmonary Function Test/Forced Expiratory Volume 1", "Quality of life", "Questionnaires", "Recommendation", "Research", "Resources", "Respiratory Signs and Symptoms", "Respiratory Tract Infections", "Risk", "Risk Factors", "Seasons", "Self Efficacy", "Self Management", "Service delivery model", "Severities", "Smoking Prevention", "Social outcome", "Spirometry", "Testing", "Tobacco", "Tobacco smoke", "Tobacco smoking behavior", "Vaccination", "Vaccines", "Vacuum", "Viral", "Virus Diseases", "Wheezing", "World Health Organization", "aged", "ambient air pollution", "chronic care model", "chronic respiratory disease", "comparison control", "disability-adjusted life years", "effectiveness-implementation RCT", "effectiveness/implementation hybrid", "eligible participant", "experience", "high efficiency particulate air filter", "human centered design", "implementation context", "implementation evaluation", "implementation outcomes", "implementation science", "improved", "indexing", "indoor air", "indoor exposure", "influenza virus vaccine", "intervention effect", "intervention mapping", "life span", "low and middle-income countries", "lung health", "member", "multi-component intervention", "multidisciplinary", "nicotine replacement", "pedomet" ], "approved": true } }, { "type": "Grant", "id": "15617", "attributes": { "award_id": "1R01AI189657-01", "title": "Synergistic Nanobodies for Pandemic Preparedness", "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": 6115, "first_name": "DIPANWITA", "last_name": "Basu", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-02-24", "end_date": "2030-01-31", "award_amount": 867563, "principal_investigator": { "id": 32114, "first_name": "JOHN D.", "last_name": "AITCHISON", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32115, "first_name": "MICHAEL P", "last_name": "ROUT", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 763, "ror": "https://ror.org/0420db125", "name": "Rockefeller University", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "Betacoronaviruses (beta-CoVs), including SARS-CoV-1, MERS-CoV, and SARS-CoV-2, have reshaped our understanding of pandemic preparedness. These viruses demonstrate a remarkable ability to mutate and evade defenses, continuing to infect populations worldwide despite extensive vaccination efforts and antiviral therapies. The chameleon-like nature of SARS-CoV-2, particularly its modifications to the Spike protein, consistently outpaces existing countermeasures, necessitating new strategies. This proposal introduces a pioneering class of nanobodies (Nbs), engineered from the immune system of llamas, designed to provide comprehensive protection against all beta-CoVs. These biologics not only advance treatment but also signify a pivotal step in pandemic preparedness, equipping us to outpace the relentless evolution of beta-CoVs. Our innovation lies in developing multivalent, synergistic combinations of broad-spectrum, high-efficacy Nbs. By harnessing these combinations, we amplify their efficacy and scope, concurrently increasing their resistance to viral mutations. Administered intranasally or directly to the lungs, these Nbs serve as both prophylactics and therapeutic agents. Our first Aim is to strategically expand upon our proven repertoires to identify, isolate, and characterize a much larger and more diverse repertoire of Nbs that collectively are strongly neutralizing across the beta-CoVs. We will use cutting-edge methods to produce diverse Nbs from llamas exposed to spike proteins of various beta- CoVs, selecting those with high affinity, specificity, and stability. We aim to discover synergistic, escape-resistant Nb pairs through combination testing and structural analysis. In our second Aim, we will optimize critical parameters important for developing broadly neutralizing Nb combinations and derivatives for human use. We will evaluate the in vivo synergistic potential of Nbs targeting major threats like MERS-CoV and SARS-CoV-2, and engineer Nbs to optimize their properties and efficacy in preparation for clinical trials. Deploying these pre- programmed Nbs at an outbreak's onset will protect first responders and medical personnel, reduce hospital surges, limit transmission, and buy time for new vaccine development and rollout. They will also provide crucial support to immunocompromised individuals, safeguarding the most vulnerable from the start. We hypothesize that our synergistic Nb combinations will introduce new beta-CoV neutralization methods, effectively prevent and treat infections, and maintain efficacy against emerging beta-CoV threats.", "keywords": [ "2019-nCoV", "Acceleration", "Affinity", "Anti-viral Therapy", "Antibodies", "Binding", "Biological Products", "Cells", "Clinical Trials", "Collaborations", "Development", "Disease Outbreaks", "Ensure", "Evolution", "Exhibits", "Exposure to", "Future", "Health Personnel", "Hospitals", "Human", "Immunocompromised Host", "Individual", "Infection", "Inhalators", "Intranasal Administration", "Llama", "Lung", "Membrane Glycoproteins", "Methods", "Middle East Respiratory Syndrome Coronavirus", "Modification", "Monoclonal Antibodies", "Mutate", "Mutation", "Nature", "Outcome", "Population", "Preparation", "Prevention", "Property", "Proteins", "Readiness", "Resistance", "SARS coronavirus", "SARS-CoV-2 variant", "Shapes", "Specificity", "Sum", "System", "Testing", "Therapeutic Agents", "Time", "Vaccination", "Variant", "Viral", "Virus", "betacoronavirus", "biophysical properties", "design", "first responder", "global health", "immunoengineering", "immunogenicity", "in vivo", "innovation", "insight", "nanobodies", "nanoengineering", "novel vaccines", "pandemic disease", "pandemic preparedness", "prevent", "prophylactic", "respiratory virus", "stem", "synergism", "transmission process", "vaccine development", "vaccine distribution" ], "approved": true } }, { "type": "Grant", "id": "15612", "attributes": { "award_id": "1U54AG089326-01", "title": "Biospecimen Analysis", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Aging (NIA)" ], "program_reference_codes": [], "program_officials": [], "start_date": "2025-02-01", "end_date": "2030-01-31", "award_amount": 796905, "principal_investigator": { "id": 20884, "first_name": "Suman Ranjan", "last_name": "Das", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 456, "ror": "https://ror.org/05dq2gs74", "name": "Vanderbilt University Medical Center", "address": "", "city": "", "state": "TN", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 456, "ror": "https://ror.org/05dq2gs74", "name": "Vanderbilt University Medical Center", "address": "", "city": "", "state": "TN", "zip": "", "country": "United States", "approved": true }, "abstract": "The Biospecimen Analysis Core (BAC) of our Vanderbilt-coordinated human Virome Characterization Center (V2C2) is designed to enable the composition and complexity of a host-contextualized human virome (replicating and integrated) to be rapidly and cost-effectively generated with high-quality across multiple tissue types. In Aim 1, the BAC will receive and characterize the virome across a range of biospecimen types from our Biospecimen Collection Core (BCC). This process will include viral sequencing (whole metagenomics/metatranscriptomic sequencing), validation studies (digital PCR and capture-based methods, among them), and host response characterization, including tropism studies (via bulk and single-cell RNA-seq approaches, in vitro infection studies) and assessments of host inflammatory state (targeted proteomics). In Aim 2, the BAC will establish standard operating procedures for metadata, analytics, and quality control and assessment, including consortium-wide benchmarking and reproducibility of critical assays to investigate and limit variability from the collection point to the final analysis. The BAC will synergize with all other V2C2 cores via (1) scientific counsel to the administrative core and the wider HVP on the development of new technologies based on HVP results to enable viral screening at the epidemiologic scale; (2) enabling collaborative projects with other HVP efforts (e.g., tropism studies with Functional Interactions projects; RFA-RM-23-017), augmenting essential human translational biology in the HVP. Our BCC has several fundamental strengths that ensure success, including: (1) leadership structure with extensive expertise in large epidemiologic efforts: Dr. Simon Mallal (a renowned physician-scientist who works on viral-host co-evolution and genetic interactions, Director of the Vanderbilt VANTAGE sequencing core), Dr. Jane Freedman (a leader in sequencing and proteomics and large NIH studies, including Common Fund efforts), and Dr. Suman Das (a human molecular virologist with extensive experience in methods development and discovery in human virology), all of whom have a track-record of collaboration in large NIH-funded human studies; (2) deep expertise in viral sequencing: Dr. Das and Mallal have sequenced many classes of human viruses (e.g., influenza, RSV, HIV, HCV, HBV, EBV, enteroviruses, rotavirus, norovirus, Ebola, Zika, coronaviruses, resulting in >400K Genbank accessions); (3) expertise in methods development in metagenomics: in this process, they have developed many new laboratory and computational methods enabling capture of the human virome (replicating eukaryotic RNA/DNA viruses and phages) and host integration; (5) rapid assessment of host response characteristics (including mucosal immunity, relation with other commensal microbial flora, and emerging types for characterization [e.g., extracellular vesicles, platelets, proteomics]); (6) large, NIH-funded core laboratory structures that enable cost-efficient BAC conduct (e.g., NHLBI TOPMed 2.0 Core; Vanderbilt resources led PD Mallal/PI Das). Successful completion will provide HVP with a comprehensive host-viral characterization for consortium-wide integration.", "keywords": [ "Adult", "Architecture", "Bacteriophages", "Benchmarking", "Biological Assay", "Biological Markers", "Biology", "Blood Platelets", "Cell Culture Techniques", "Cells", "Characteristics", "Child", "Child Health", "Collaborations", "Collection", "Communicable Diseases", "Communication", "Computing Methodologies", "Coronavirus", "Counseling", "DNA Sequencing Facility", "DNA Viruses", "Data", "Data Analyses", "Data Coordinating Center", "Development", "Ebola", "Ensure", "Enterovirus", "Epidemiology", "Funding", "Genbank", "Genetic", "Genome", "Genomics", "Goals", "HIV", "Health", "Hepatitis B Virus", "Hepatitis C virus", "High-Throughput Nucleotide Sequencing", "Human", "Human Genome", "Human Herpesvirus 4", "Immune response", "In Vitro", "Infection", "Inflammatory", "Influenza", "Institution", "Investments", "Laboratories", "Leadership", "Meta-Analysis", "Metadata", "Metagenomics", "Methods", "Mission", "Molecular", "Mucosal Immunity", "National Heart Lung and Blood Institute", "Norovirus", "Organoids", "Outcome", "Physicians", "Procedures", "Process", "Proteomics", "Quality Control", "RNA", "Reporting", "Reproducibility", "Resolution", "Resources", "Rotavirus", "Sampling", "Scientist", "Site", "Source", "Specific qualifier value", "Standardization", "Structure", "Techniques", "Tissues", "Trans-Omics for Precision Medicine", "Tropism", "United States National Institutes of Health", "Validation", "Viral", "Virus", "Work", "ZIKA", "biobank", "cost", "cost efficient", "data submission", "design", "digital", "experience", "extracellular", "extracellular vesicles", "human virome", "integration site", "interoperability", "metagenomic sequencing", "metatranscriptomics", "method development", "microbial", "microbial host", "microbiota", "multiple omics", "new technology", "screening", "single-cell RNA sequencing", "success", "synergism", "validation studies", "virology", "virome" ], "approved": true } }, { "type": "Grant", "id": "15616", "attributes": { "award_id": "1R01AI185617-01A1", "title": "RNA epigenetic modifications in 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": 27781, "first_name": "Mary Katherine Bradford", "last_name": "Plimack", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-02-01", "end_date": "2030-01-31", "award_amount": 582618, "principal_investigator": { "id": 26224, "first_name": "Jianrong", "last_name": "Li", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32113, "first_name": "Mark E.", "last_name": "Peeples", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 778, "ror": "", "name": "OHIO STATE UNIVERSITY", "address": "", "city": "", "state": "OH", "zip": "", "country": "United States", "approved": true }, "abstract": "Post-transcriptional RNA modifications are widespread and regulates numerous biological processes including RNA metabolism, protein translation, gene expression, and disease. Among the more than 180 types of RNA modifications, N6-methyladenosine (m6A) and pseudouridine (Ψ) are the two most prevalent. The m6A modification is catalyzed by the host RNA methyltransferase complex of METTL3 and METTL14. The Ψ modification is converted from the nucleoside uridine (U) by the host pseudouridine synthases (PUSs). Despite being discovered in the 1950s, the biological functions of the m6A and Ψ modifications in the context of virus infection remain poorly understood. This project is built upon our recent development of high throughput sequencing techniques that have enabled mapping of m6A and ψ sites at a single base resolution. Using these techniques, we discovered that SARS-CoV-2 RNA isolated from well-differentiated primary human bronchial epithelial (HBE) cultures that include their in vivo target cells is heavily modified with m6A and ψ. In addition, we have found that depletion of several m6A and ψ writer proteins decreases SARS-CoV-2 replication in HBE culture. These findings led to our hypothesis that SARS-CoV-2 acquires m6A and Ψ modifications in its RNA to maximize virus replication. Thus, the goal of this project is to determine the mechanisms by which RNA m6A and ψ modifications modulate SARS-CoV-2 replication, gene expression, innate and adaptive immunity, and pathogenesis. In Aim 1, we will use a CRISP-Cas 9 technique to knock out host RNA m6A methyltransferases and PUSs in HBE cultures to determine the role(s) of m6A and Ψ modifications in the SARS-CoV-2 life cycle. We will also use knockout mice to examine the role(s) of m6A and Ψ modification in SARS-CoV-2 replication in vivo. We will also identify the specific PUS enzyme(s) that catalyze pseudouridylation on SARS-CoV-2 RNA. In Aim 2, we will mutate the m6A and/or ψ sites in the SARS-CoV-2 genomic RNA and use the reverse genetics system to generate recombinant SARS-CoV-2 lacking m6A and/or ψ modification sites and use them to determine the roles of m6A and ψ modifications on viral RNA metabolism, encapsidation, RNA replication, viral protein translation, and innate immunity. In Aim 3, we will determine whether m6A and ψ modifications modulate mucosal and adaptive immune responses of SARS-CoV-2 live attenuated vaccines (LAVs) and determine whether LAVs lacking m6A and/or ψ are more immunogenic in golden Syrian hamsters. Upon completion of this project, we expect to have unravelled the mechanisms by which m6A and Ψ modifications modulate the SARS- CoV-2 replication cycle, leading to the development of novel and improved LAVs and therapies for COVID-19 that target these RNA modifications.", "keywords": [ "2019-nCoV", "Adenosine", "Anti-viral Agents", "Anti-viral Therapy", "Antibodies", "Attenuated", "Attenuated Vaccines", "B-Lymphocytes", "Biological Process", "COVID-19", "COVID-19 treatment", "COVID-19 vaccine", "Carbon", "Cells", "Cessation of life", "Collaborations", "Complementary DNA", "Complex", "Development", "Disease", "Effectiveness", "Enzymes", "Epigenetic Process", "Exposure to", "Gene Expression", "Genetic Recombination", "Genetic Transcription", "Goals", "Hamsters", "High-Throughput Nucleotide Sequencing", "High-Throughput RNA Sequencing", "Human", "Immune response", "Infection", "Innate Immune Response", "Intramuscular", "Isomerism", "Knock-out", "Knockout Mice", "Life Cycle Stages", "Maps", "Mediating", "Mesocricetus auratus", "Methylation", "Methyltransferase", "Modeling", "Modification", "Mucosal Immune Responses", "Mucous Membrane", "Mutate", "Natural Immunity", "Nucleosides", "Nucleotides", "Pathogenesis", "Pharmaceutical Preparations", "Positioning Attribute", "Post-Transcriptional RNA Processing", "Process", "Proteins", "Pseudouridine", "Public Health", "RNA", "RNA Stability", "RNA metabolism", "RNA purification", "RNA replication", "Reader", "Recombinants", "Resolution", "Role", "Rotation", "SARS-CoV-2 immunity", "SARS-CoV-2 infection", "SARS-CoV-2 variant", "Signal Transduction", "Site", "Small Interfering RNA", "Societies", "System", "T-Lymphocyte", "Techniques", "Therapeutic Agents", "Translations", "Uridine", "Vaccines", "Viral Pathogenesis", "Viral Proteins", "Virus Diseases", "Virus Replication", "adaptive immune response", "adaptive immunity", "attenuation", "base", "bronchial epithelium", "genomic RNA", "immunogenic", "improved", "in vivo", "knock-down", "mRNA Translation", "novel", "novel therapeutics", "novel vaccines", "obligate intracellular parasite", "prevent", "public health relevance", "reverse genetics", "small hairpin RNA", "targeted treatment", "transmission process", "vaccine delivery", "variants of concern", "viral RNA" ], "approved": true } } ], "meta": { "pagination": { "page": 2, "pages": 1392, "count": 13920 } } }