Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1385&sort=start_date
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=start_date", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1397&sort=start_date", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1386&sort=start_date", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1384&sort=start_date" }, "data": [ { "type": "Grant", "id": "15531", "attributes": { "award_id": "1R35NS137447-01", "title": "Expanding insights into FTD disease mechanisms", "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": 23658, "first_name": "FRANK PAUL", "last_name": "Shewmaker", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-15", "end_date": "2032-11-30", "award_amount": 1138538, "principal_investigator": { "id": 20546, "first_name": "LEONARD", "last_name": "PETRUCELLI", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1414, "ror": "", "name": "MAYO CLINIC JACKSONVILLE", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1414, "ror": "", "name": "MAYO CLINIC JACKSONVILLE", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true }, "abstract": "Frontotemporal lobar degeneration (FTLD), which underlies frontotemporal dementia (FTD), encompasses a group of disorders with significant genetic, clinical, and neuropathological heterogeneity. FTLD is also genetically and pathologically associated with the motor neuron disease amyotrophic lateral sclerosis (ALS), with some patients developing both disorders. Understanding the diverse mechanisms governing FTLD pathogenesis is a fundamental area of interest of my research program, and we pursue this goal by asking impactful questions and applying innovative techniques. To accelerate scientific discovery, we have adopted a comprehensive approach that investigates multiple FTLD mechanisms driven by key molecular players like C9orf72, TDP-43, progranulin, tau and, more recently, TMEM106B. We also place great emphasis on translational research geared towards identifying much needed biomarkers and therapies, an area of particular importance given that there exists no treatment for FTLD. Since the funding of my current R35 at the end of 2016, my group has uncovered seminal findings related to the pathomechanisms mediated by FTLD-associated mutations in C9orf72 and GRN and shed crucial insight into the consequences of pathogenic TDP-43 and tau deposition in the brain. These findings have garnered high-impact publications in Science, Nature, and Cell and inspired new and ongoing avenues of research in my lab. The flexibility afforded by the R35 funding opportunity also allowed us to branch into other related topics and tackle urgent issues in the broader neuroscience field, including the need for biomarkers and mouse models for distinct repeat-associated disorders like spinocerebellar ataxias and the recent pressing need for tools to study and understand COVID-19 and its impact on the brain. Our productivity is influenced by the excellent research environment fostered at Mayo Clinic, which brings together highly interactive and devoted neurobiologists, geneticists, neuropathologists and physician scientists, the diversity of my team, and the numerous collaborations we have forged with world-renowned experts in the field, as well as our dedication to stewardship and the sharing of information and resources with the scientific community at large. Drawing from our past work on FTLD, we now propose to explore current cutting-edge questions related to: (1) the molecular underpinnings of TDP-43 localization and function and the downstream consequences of its dysfunction in disease, (2) the mechanisms underlying cryptic splicing in TDP-43 proteinopathies and the role of cryptic RNA and proteins in FTLD, (3) the role of the endo-lysosomal system in the development of TDP-43 pathology and neurodegeneration, and (4) the emerging role of TMEM106B fibrillogenesis in diverse neurodegenerative diseases including TDP-43 proteinopathies and tauopathies. We will use a combination of mouse and induced pluripotent stem-cell modeling, transcriptomics, proteomics, histology, and human tissue analyses to carry-out our proposed studies and address new and potentially transformative ideas as they emerge.", "keywords": [ "Acceleration", "Address", "Adopted", "Affect", "Amyotrophic Lateral Sclerosis", "Area", "Behavior", "Biological Markers", "Brain", "C9ORF72", "COVID-19", "Cells", "Clinic", "Clinical", "Collaborations", "Communities", "Dedications", "Deposition", "Development", "Disease", "Disease Progression", "Environment", "Fostering", "Frontotemporal Dementia", "Frontotemporal Lobar Degenerations", "Functional disorder", "Funding", "Funding Opportunities", "Genetic", "Goals", "Heterogeneity", "Histology", "Language", "Mediating", "Molecular", "Monitor", "Motor Neuron Disease", "Mus", "Mutation", "Nature", "Nerve Degeneration", "Neurodegenerative Disorders", "Neurosciences", "PGRN gene", "Pathogenesis", "Pathogenicity", "Pathologic", "Pathology", "Patients", "Personality", "Physicians", "Process", "Productivity", "Proteins", "Proteomics", "Publications", "RNA", "RNA Splicing", "Research", "Resources", "Role", "Science", "Scientist", "Seminal", "Spinocerebellar Ataxias", "System", "Tauopathies", "Techniques", "Translational Research", "Work", "fibrillogenesis", "flexibility", "forging", "human tissue", "improved", "induced pluripotent stem cell", "innovation", "insight", "interest", "mouse model", "neuropathology", "novel", "patient prognosis", "prevent", "programs", "protein TDP-43", "stem cell model", "tau Proteins", "tool", "transcriptomics" ], "approved": true } }, { "type": "Grant", "id": "15532", "attributes": { "award_id": "1R21NS140036-01", "title": "Utilizing a novel hamster model to determine neurologic and behavioral abnormalities of offspring from mothers infected with SARS-CoV-2", "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": 6896, "first_name": "WILLIAM PATRICK", "last_name": "Daley", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-15", "end_date": "2026-11-30", "award_amount": 240000, "principal_investigator": { "id": 32072, "first_name": "Eliseo A", "last_name": "Eugenin", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32073, "first_name": "Kenneth Steven", "last_name": "Plante", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 851, "ror": "", "name": "UNIVERSITY OF TEXAS MED BR GALVESTON", "address": "", "city": "", "state": "TX", "zip": "", "country": "United States", "approved": true }, "abstract": "A novel coronavirus, severe acute respiratory syndrome 2 (SARS-CoV-2), emerged in 2019 and led to the worldwide COVID-19 pandemic with over 773 million human infections and 7 million deaths by the end of 2023. Four years later, the full implications of this pandemic remain unclear. Though the acute syndrome has been extensively characterized, more cryptic complications such as long-COVID and neuro-PASC demonstrate that this illness still requires intensive study. Additionally, maternal infection has been linked to negative fetal outcomes including stillbirth. Recent studies implicate SARS-CoV-2 in neurologic aberrations of offspring born to infected mothers. It is crucial that these clinical findings are confirmed through laboratory studies to interrogate the mechanism of any such impacts. A proactive approach to this issue can help alleviate the societal impact of a large influx of children potentially exhibiting neurodevelopmental issues as a result of gestational COVID-19 exposure. As such, the objective of this study is to develop the golden Syrian hamster model to examine the role of maternal infection. The hamster model has been used to great effect in characterizing COVID-19 variants as it does not require adapted virus, demonstrates human-like illness and pathology, and is capable of transmission. Additionally, our group has shown its functional role in a common neuro-PASC sign of illness, anosmia. Utilizing classical virology, molecular biology, histopathology, and extensive neuroimaging, we also expect to gain insight into the mechanisms involved. We further plan on utilizing behavioral studies that we have adapted for hamsters to determine long-term neurodevelopment impacts on the offspring. We will accomplish this through two aims. In Specific Aim 1, we will focus on the impact of maternal infection in utero. Initial studies will focus on the direct effects of maternal infection on the female reproductive tract and developing fetus. Additionally, we will determine which tissues are capable of being productively infected and whether vertical transmission occurs. We will also determine the inflammatory state of the placenta and fetus. Our multidisciplinary team will do an in-depth analysis on neurodevelopment to identify any acute fetal neurologic aberrations resulting from maternal infection. In Specific Aim 2, we will explore the behavioral and neurologic implications of maternal infection on the resulting offspring. We have optimized tests for depression, muscle weakness, and cognition/memory in the golden Syrian hamster model. We expect that even in the absence of acute fetal abnormality or vertical transmission, the inflammatory state of the infected dams will cause detrimental long-term neurological impacts in the resulting pups analogous to those reported in human offspring. In addition to the behavioral testing, we will perform extensive histopathologic analysis, neuroimaging, and c-Fos straining to assess the impact of maternal infection. The proposed studies will generate a novel maternal-fetal hamster model of COVID-19. Our results can be utilized to better prepare public health entities to the long-term societal impacts of COVID-19 maternal infection and to provide a powerful tool to the research community for mechanistic and interventional studies.", "keywords": [ "2019-nCoV", "Acute", "Address", "Animal Model", "Anosmia", "Behavioral", "Brain", "COVID-19", "COVID-19 impact", "COVID-19 pandemic", "Cells", "Cessation of life", "Child", "Clinical", "Clinical Research", "Cognition", "Communities", "Defect", "Development", "Diagnosis", "Exhibits", "FOS gene", "Fetal Development", "Fetus", "Goals", "Hamsters", "Histopathology", "Human", "Immune", "Immunocompetence", "Impairment", "Incidence", "Infant", "Infection", "Inflammatory", "Inflammatory Response", "Influenza A virus", "Intervention Studies", "Investigation", "Kinetics", "Knowledge", "Laboratory Study", "Late pregnancy", "Life", "Link", "Long COVID", "Long-Term Effects", "Longitudinal Studies", "Medical", "Memory", "Mental Depression", "Mental Health", "Mental disorders", "Mesocricetus auratus", "Modeling", "Molecular Biology", "Mothers", "Muscle Weakness", "Nervous System Physiology", "Neurodevelopmental Disorder", "Neurologic", "Neurologic Signs", "Neurologic Symptoms", "Neurological observations", "Outcome", "Ovary", "Pathology", "Persons", "Physiological", "Placenta", "Post-Acute Sequelae of SARS-CoV-2 Infection", "Pregnancy", "Productivity", "Public Health", "Pulmonary Pathology", "Readiness", "Recording of previous events", "Reporting", "Reproducibility", "Reproduction", "Research", "Risk", "Rodent Model", "Role", "SARS coronavirus", "SARS-CoV-2 exposure", "SARS-CoV-2 infection", "SARS-CoV-2 variant", "Syndrome", "Testing", "Therapeutic", "Thrombus", "Tissues", "Uterus", "Vagina", "Vertical Transmission", "Virus", "Virus Diseases", "Work", "acute COVID-19", "behavior test", "behavioral study", "clinically relevant", "clinically significant", "congenital infection", "cytokine", "economic impact", "female reproductive system", "female reproductive tract", "fetal", "immune activation", "in utero", "inflammatory marker", "insight", "mortality", "multidisciplinary", "neurodevelopment", "neuroimaging", "neurologic sequelae of COVID-19", "novel", "novel coronavirus", "offspring", "pandemic disease", "pup", "reproductive", "stem", "stillbirth", "tool", "transmission process", "vaccine evaluation", "viral transmission", "virology" ], "approved": true } }, { "type": "Grant", "id": "15534", "attributes": { "award_id": "1R01AG090337-01", "title": "CD38, T cells and post viral lung sequelae during aging", "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": [ { "id": 23647, "first_name": "MULUALEM ENYEW", "last_name": "Tilahun", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-15", "end_date": "2029-11-30", "award_amount": 639740, "principal_investigator": { "id": 20818, "first_name": "Jie", "last_name": "Sun", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1426, "ror": "", "name": "MAYO CLINIC ROCHESTER", "address": "", "city": "", "state": "MN", "zip": "", "country": "United States", "approved": true } ] }, "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": "Summary/Abstract In light of the widespread and devastating impact of the SARS-CoV-2 pandemic, a significant number of individuals have been observed to develop chronic lung conditions characterized by persistent inflammation and fibrosis after recovering from acute COVID-19. Furthermore, recent studies indicate that such chronic lung issues are also prevalent following other respiratory viral infections, such as influenza. A critical gap in our understanding persists regarding the cellular and molecular mechanisms that underlie the development of chronic lung sequelae post-primary viral pneumonia. This gap in knowledge poses a potential obstacle in creating effective treatments for patients suffering from chronic lung fibrosis triggered by SARS-CoV-2 and other respiratory viral infections. Our research has revealed that CD8 tissue resident memory (TRM) cells exhibit high levels of the NAD+ ectoenzyme CD38. This enzyme is essential for the formation and maintenance of CD8 TRM cells after primary respiratory viral infections. In this proposal, we aim to explore the hypothesis that targeting CD38 could dampen aberrant CD8 TRM accumulation in aged hosts, thereby mitigating age-associated chronic lung fibrosis following viral pneumonia. If our hypothesis is correct, the data generated in this study will not only provide mechanistic insights as to how lung sequelae develop after viral pneumonia including COVID-19, but could also pave the way for targeted immunotherapies aiming to preserve lung function after acute viral pneumonia in the elderly.", "keywords": [ "2019-nCoV", "Ablation", "Acute", "Adult", "Age", "Age Years", "Aging", "Attenuated", "Biotechnology", "CD8B1 gene", "COVID-19", "COVID-19 pandemic", "COVID-19 pandemic effects", "COVID-19 pneumonia", "Cells", "Cessation of life", "Chronic", "Chronic Disease", "Chronic lung disease", "Clinical", "Clinical Data", "Clinical Research", "Clinical Trials", "Data", "Data Correlations", "Development", "Elderly", "Enzymes", "Exhibits", "Fibrosis", "Future", "Immunity", "Immunology", "Immunotherapy", "Impairment", "Individual", "Industrialization", "Infection", "Inflammation", "Inflammatory", "Influenza", "Injury", "Knowledge", "Light", "Lung", "Maintenance", "Memory", "Metabolic", "Molecular", "Morbidity - disease rate", "Outcome", "Pathway interactions", "Patients", "Persons", "Preventive", "Primary Infection", "Public Health", "Publishing", "Pulmonary Fibrosis", "Pulmonary Inflammation", "Pulmonary Pathology", "Recovery", "Regulation", "Research", "Residual state", "Resolution", "SARS-CoV-2 infection", "Science", "Survivors", "T-Lymphocyte", "Testing", "Therapeutic Intervention", "Tissues", "Viral", "Viral Pneumonia", "Viral Respiratory Tract Infection", "acute COVID-19", "acute infection", "age related", "aged", "aging population", "antimicrobial", "cytotoxicity", "effective therapy", "in vivo", "influenzavirus", "insight", "lung preservation", "mortality", "pathogen", "pre-clinical", "prevent", "pulmonary function", "respiratory", "response", "severe COVID-19", "tissue resident memory T cell", "translational potential" ], "approved": true } }, { "type": "Grant", "id": "15660", "attributes": { "award_id": "2413062", "title": "NSF-ANR MCB/PHY: Virus self-assembly, from test tube to cell cytoplasm", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Unknown", "Molecular Biophysics" ], "program_reference_codes": [], "program_officials": [ { "id": 15289, "first_name": "Wilson", "last_name": "Francisco", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-15", "end_date": null, "award_amount": 987566, "principal_investigator": { "id": 32168, "first_name": "William", "last_name": "Gelbart", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 3324, "first_name": "Roya", "last_name": "Zandi", "orcid": null, "emails": "[email protected]", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 153, "ror": "", "name": "University of California-Riverside", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true } ] } ], "awardee_organization": { "id": 151, "ror": "", "name": "University of California-Los Angeles", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Coming out of the most severe and destructive viral pandemic of the past 100 years, the importance of understanding how viruses “work” is clear. Most viruses – including polio, yellow fever, Dengue, and SARS, etc. – have RNA genomes that are quickly turned or “translated” into viral proteins in host cells that self-assembled into new virus particles called capsids. Elucidating how this process happens is a high priority for preventing and treating these infections. This project sets out to connect in vivo experiments carried out in live cells with in vitro experiments carried out in a test tube with purified viral capsid proteins and RNA genome. While test tube studies allow for full control of the types and numbers of components and solution conditions in which they are interacting, live cells studies, on the other hand, involve viral RNA and capsid proteins in the presence of many unknown components whose effects on RNA translation and self-assembly into capsids have not yet been determined. The fundamental understanding that results from this research will enhance the ability to develop anti-viral treatments. Graduate students will be trained in an inter-/cross-disciplinary range of physical, chemical, biological, and translational medicine concepts and methods. Active outreach efforts aim at enhancing interest and understanding of science amongst budding scientists and lay persons of all kinds will be conducted. This project will be performed by an international collaboration between five different research groups in the US and France, each specializing in different experimental and theoretical techniques and each having extensive experience with one or the other of the plant (cowpea chlorotic mottle virus [CCMV]) and mammalian (hepatitis B [HepB]) viruses under study. These viruses were chosen because how significantly they differ in their host cell and capsid structure, so that general principles of viral self-assembly can be established. It is the goal of this project to elucidate the differences between in vitro and in cellulo viral processes by progressively adding to RNA and capsid protein a series of molecules that play key roles in the viral “life” cycle, mimicking the crowded interior of the cell. Using cell-free cytoplasmic (ribosome-rich) extract, viral RNA will be translated into protein products and the time course of capsid assembly will be investigated by a combination of experimental techniques, including magnetic resonance, X-ray scattering, and fluorescence and electron microscopies. Coarse-grained molecular dynamics computations and phenomenological theory will be used to analyze these kinetic data and to compare with what is learned using the same experimental techniques applied to corresponding virus assembly in test tubes, where all concentrations and solution conditions are controlled. This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigator and ANR funds the partners in France. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "15523", "attributes": { "award_id": "1K99AI182458-01A1", "title": "Elucidating a novel respiratory-mammary axis of T cell immunity", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 6125, "first_name": "Timothy A.", "last_name": "Gondre-Lewis", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-16", "end_date": "2026-11-30", "award_amount": 114976, "principal_investigator": { "id": 32064, "first_name": "Blair", "last_name": "Armistead", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 732, "ror": "https://ror.org/01njes783", "name": "Seattle Children's Hospital", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "Breastfeeding is associated with immunological benefits that persist beyond infancy, including reduced risk of respiratory infection. While these benefits are often attributed to immunoglobulins and antimicrobial compounds, human milk is also rich in T cells whose function is unknown. A central goal of my research career is to elucidate the protective function of breastmilk T cells against infant respiratory infection. To this end, I propose to investigate the respiratory-mammary axis of cellular immunity and its role in the establishment, retention, and response of tissue resident memory T cells (TRM) in the lactating breast. I hypothesize that i) maternal exposure to respiratory infections results in priming of T cell populations that go on to seed TRM in both the breast and the respiratory tract and ii) antigen exposure via saliva of the nursing infant drives persistence of TRM in the lactating breast. I will use samples from a cohort of mother infant pairs, which includes breastmilk cells (BMC), nasal mucosal cells (NMC), and peripheral blood mononuclear cells (PBMC). In Aim 1, I will investigate whether T cells resident to the upper respiratory tract and lactating breast are derived from a shared cellular population by defining the transcriptional and clonal overlap of T cells from BMC and NMC using single cell RNA sequencing with paired T cell receptor (TCR)αβ sequencing. In Aim 2, I will evaluate the contribution of infant respiratory infection and coinciding maternal and infant respiratory infection on the frequency and functional state of breastmilk T cell subsets. To do this, I will enroll mother-infant pairs seeking care at Seattle Children’s Urgent Care clinics with PCR-confirmed infant SARS-CoV-2 or influenza A. BMC from acute and convalescent timepoints will be evaluated by high-parameter flow cytometry for T cell immunophenotyping. In Aim 3, I will interrogate breastmilk antigen-specific TRM responses in the setting of maternal and infant respiratory syncytial virus (RSV) infection. I will enroll mother-breastfed infant pairs who present to urgent care with PCR-confirmed infant RSV infection in which i) both the mother and infant are infected with RSV or ii) only the infant is infected, I will stimulate maternal BMC from these pairs (along with those from healthy controls) with an RSV peptide pool and assess the frequency and phenotype of T cells expressing activation-induced markers (AIM) using flow cytometry. These studies will elucidate the establishment, retention, and response of TRM in the lactating breast, with relevance to future work to discern how these cells may protect against infant respiratory infection. The proposed work will take place at Seattle Children’s Research Institute under the co-mentorship of Dr. Whitney Harrington and Dr. Alexis Kaushansky. I have additionally recruited a scientific advisory committee who will support my success in achieving the proposed aims; my short-term objectives of gaining skill/expertise in mucosal T cell biology, human study design, and computational biology; and my transition to an independent faculty position. In short, this award will empower me to achieve my long-term goal of leading a research program focused on infection and immunity during pregnancy, post-partum, and infancy.", "keywords": [ "2019-nCoV", "Acute", "Advisory Committees", "Antibodies", "Antigens", "Award", "Breast", "Breast Feeding", "Breastfed infant", "Cells", "Cellular Immunity", "Cellular biology", "Child", "Childhood", "Circulation", "Clinic", "Computational Biology", "Cytoprotection", "Data", "Enrollment", "Exhibits", "Exposure to", "Faculty", "Flow Cytometry", "Frequencies", "Future", "Gene Expression Profile", "Gene Expression Regulation", "Genetic Transcription", "Glycoproteins", "Goals", "Homing", "Human Milk", "Immunity", "Immunization", "Immunoglobulins", "Immunologics", "Immunophenotyping", "Incidence", "Individual", "Infant", "Infection", "Influenza A virus", "Intramuscular", "Lactation", "Life", "Lung", "Mammary Gland Parenchyma", "Maternal Exposure", "Memory", "Mentorship", "Mothers", "Mucosal Immunity", "Mucous Membrane", "Nursing infant", "Peptides", "Peripheral Blood Mononuclear Cell", "Phenotype", "Population", "Positioning Attribute", "Postpartum Period", "Pregnancy", "Production", "Proliferating", "Receptor Activation", "Research", "Research Design", "Research Institute", "Respiratory Syncytial Virus Infections", "Respiratory Syncytial Virus Vaccines", "Respiratory System", "Respiratory Tract Infections", "Respiratory syncytial virus", "Risk", "Role", "Saliva", "Sampling", "Severities", "Site", "Source", "Structure of mucous membrane of nose", "T cell infiltration", "T cell response", "T memory cell", "T-Cell Activation", "T-Cell Receptor", "T-Lymphocyte", "T-Lymphocyte Subsets", "Technology", "Testing", "Tissues", "Upper Respiratory Infections", "Upper respiratory tract", "Upregulation", "Vaccination", "Vaccines", "Viral Respiratory Tract Infection", "Work", "acute infection", "alpha-beta T-Cell Receptor", "antimicrobial", "care seeking", "career", "cell bank", "cohort", "cytokine", "empowerment", "human study", "improved", "infancy", "infant infection", "insight", "live attenuated influenza vaccine", "mammary", "mucosal site", "novel", "pathogenic virus", "peripheral blood", "programs", "protective effect", "recruit", "residence", "respiratory", "respiratory pathogen", "response", "single-cell RNA sequencing", "skills", "success", "tissue resident memory T cell", "urgent care", "vaccination outcome", "vaccination strategy" ], "approved": true } }, { "type": "Grant", "id": "15527", "attributes": { "award_id": "1R21AI183544-01A1", "title": "Understanding transgender women's immune and behavioral responses to seasonal COVID-19 vaccines to improve their uptake", "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": 6243, "first_name": "BROOKE ALLISON", "last_name": "Bozick", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-16", "end_date": "2026-11-30", "award_amount": 267121, "principal_investigator": { "id": 32069, "first_name": "Sara", "last_name": "Lustigman", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 1469, "ror": "https://ror.org/01xvcf081", "name": "New York Blood Center", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "Sex differences in immunity are dynamic throughout the lifespan and contribute to heterogeneity in risk of infectious diseases and response to vaccination. Sexual dimorphism is, in part, driven by sex hormones and has been demonstrated in both innate and adaptive immunity; testosterone has an immunosuppressive effect while estrogen is immunoenhancing. Thus, females tend to mount stronger immune responses, exhibit lower infection rates for a variety of pathogens, and demonstrate elevated responses to vaccination. However, the molecular mechanisms driving enhanced immunity in females are not well understood, and the degree to which exogenous sex hormones contribute to immune response is unknown. To dissect the role of female sex hormones in enhanced immunity and to broaden our understanding of sexual dimorphism in immunity and health, we propose to study the immune responses of adult transgender women (TW, individuals who identify as women but were assigned male at birth) undergoing gender-affirming hormone therapy (GAHT). This will provide a unique opportunity to understand the impact of sex hormones on the immune system generally, and more specifically, in response to the updated seasonal COVID-19 vaccines. No studies have examined interactions between COVID-19 vaccines and GAHT. We hypothesize that TW undergoing feminizing GAHT will develop enhanced immune responses that align more with their gender identity than their biological sex. Uptake of the 2023-24 seasonal COVID-19 vaccine is currently low in transgender people (12.5%), which is problematic since they are more likely to become severely ill, die, or incur COVID-related social harms (e.g., violence, job loss) if infected, however, 63% are open to it. Untangling the relationship between immune response and gender in TW may facilitate and improve evidence-based uptake of the seasonal COVID-19 vaccines in this population. Evidence from other fields (e.g., HIV) shows that TW are unlikely to use biomedical products (including vaccines) unless there exist biomedical and behavioral data specific to this population. However, to facilitate uptake and a sustained use In TW of the COVID-19 vaccines offered, we must understand not only their immunological response profile, but also their barriers, facilitators, and motivators to use. In Aim 1, humoral and cellular responses in adult TW (21-49 years) before and after immunization with the updated seasonal COVID-19 vaccine, when offered, will be compared to those elicited in clinically- and age-matched cisgender men and women with similar COVID-19 vaccine uptake and prior infections histories, and who are planning to receive the updated vaccine and be bled prior to immunization (baseline) followed by three bleeds 7-, 28- and 180-days post vaccination. In Aim 2, we will use the COM-B model and engage the TW in surveys, interviews, and in an intervention development work group before we develop a draft intervention (“OptimizeVax”) to facilitate updated seasonal COVID-19 vaccine uptake. Together, the aims comprise a critical first step towards determining if GAHT has immunoenhancing effects, and a foundation how to facilitate COVID-19 vaccines uptake by TW.", "keywords": [ "2019-nCoV", "Adult", "Age", "Antibodies", "Automobile Driving", "B-Lymphocytes", "Behavioral", "Behavioral Sciences", "COVID-19", "COVID-19 vaccination", "COVID-19 vaccine", "Cessation of life", "Clinic", "Clinical", "Communicable Diseases", "Data", "Discrimination", "Disease", "Economics", "Employee", "Epidemiology", "Estrogens", "Evidence based intervention", "Exhibits", "Fatigue", "Female", "Feminization", "Foundations", "Frequencies", "Future", "Gender", "Gender Identity", "Gonadal Steroid Hormones", "HIV", "HIV vaccine", "Health", "Health behavior", "Hemorrhage", "Heterogeneity", "Hormones", "Immune response", "Immune system", "Immunity", "Immunization", "Immunologics", "Immunology", "Immunosuppression", "Individual", "Infection", "Influenza", "Injectable", "Intervention", "Interview", "Job loss", "Literature", "Longitudinal cohort", "Modeling", "Molecular", "Morbidity - disease rate", "Natural Immunity", "Persons", "Population", "Prevalence", "Proteins", "Recording of previous events", "Research", "Risk", "Role", "SARS-CoV-2 infection", "Science", "Seasons", "Severities", "Sex Differences", "Site", "Surveys", "System", "T-Lymphocyte", "Testosterone", "Translating", "Update", "Vaccination", "Vaccine Research", "Vaccines", "Violence", "Woman", "Women&apos", "s Role", "adaptive immunity", "aged", "assigned male at birth", "behavioral response", "behavioral study", "biological sex", "cis-female", "cis-male", "cisgender", "cohort", "dynamic system", "evidence base", "experience", "female sex hormone", "gender affirming hormone therapy", "housing instability", "improved", "inclusion criteria", "infection rate", "life span", "male", "mortality", "multidisciplinary", "nonbinary", "novel", "pathogen", "prototype", "recruit", "response", "screening", "sex", "sexual dimorphism", "social", "social stigma", "therapy design", "therapy development", "transgender", "transgender men", "transgender women", "transphobia", "uptake", "vaccine acceptance", "vaccine immunogenicity", "working group" ], "approved": true } }, { "type": "Grant", "id": "15526", "attributes": { "award_id": "1R01AI188896-01", "title": "Coordination of innate and cellular mucosal immunity in SARS-CoV-2 clearance", "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": 26918, "first_name": "Michelle Marie", "last_name": "Arnold", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-20", "end_date": "2029-11-30", "award_amount": 705557, "principal_investigator": { "id": 32067, "first_name": "JACOB E", "last_name": "KOHLMEIER", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32068, "first_name": "Mehul Shamal", "last_name": "Suthar", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 265, "ror": "https://ror.org/03czfpz43", "name": "Emory University", "address": "", "city": "", "state": "GA", "zip": "", "country": "United States", "approved": true }, "abstract": "Neutralizing antibodies against SARS-CoV-2 are a strong correlate of protection against severe disease, hospitalization, and death. However, a combination of waning immunity and evolution of immune-evasive variants jeopardizes vaccine-mediated immunity. While there has been a strong research emphasis on humoral immunity, we still have a limited understanding of how mucosal innate and T cell responses contribute to SARS- CoV-2 viral control and clearance. The first few days of SARS-CoV-2 infection are marked by a transient antiviral type I interferon (IFN) response and proinflammatory cytokine and chemokine induction concomitant with mobilization of inflammatory CCR2-monocytes that traffic into the respiratory tract. Using C57BL/6 mice with a naturally occurring pathogenic SARS-CoV-2 variant (B.1.351), we previously determined the importance of CCR2- monocytes in mediating protective immunity against SARS-CoV-2. These innate immune responses are followed by the development of virus-specific antibodies and T cell responses that mediate viral control and lead to clearance. While these studies and many others have shown how aberrant immune responses at any of these stages can lead to a defect in viral control and deleterious immunopathology, most have focused exclusively on the lower respiratory tract , i.e. the lungs. In contrast, few studies have investigated the orchestration of immunity in the upper respiratory tract (URT), the site of initial virus transmission and replication, and how the individual components of the immune response contribute to viral control at this site. Here, we present evidence showing that the contributions of monocytes and T cells in promoting viral control differ between the upper and lower respiratory tract (LRT), as these responses were critical for clearance in the URT but not the LRT. We demonstrate that MYD88 signaling and inflammatory monocytes are critical for controlling early viral replication in the nasal cavity. We also found that while antigen-specific T cells infiltrate the both the nasal compartment and lungs early during infection, T cells appear to contribute a minimal role in promoting viral control and clearance in the lungs. In contrast, both CD4+ and CD8+ T cells in the nasal compartment are required for preventing persistent and culturable virus replication within nasal epithelial cells. Based on our findings, we hypothesize that the coordinated responses of inflammatory monocytes and virus-specific T cells in the upper respiratory tract are necessary to limit early viral replication and prevent viral persistence at this site. In Aim 1 we will determine the contribution of monocytes in promoting T cell responses and viral control within the respiratory tract. In Aim 2, we will define the effector mechanisms of protective mucosal T cell responses against SARS-CoV-2 infection and persistence in the URT versus LRT. Both Aims will explore these questions in the context of primary and vaccine breakthrough infections using our novel murine model of suboptimal versus protective vaccination. Overall, these studies will advance our understanding of protective mucosal innate and T cell responses that can leveraged for next-generation vaccines against SARS-CoV-2.", "keywords": [ "2019-nCoV", "ACE2", "Acute Lung Injury", "Angiotensin Receptor", "Anti-viral Response", "Antibodies", "Area", "Bronchioles", "C57BL/6 Mouse", "CCL2 gene", "CD8-Positive T-Lymphocytes", "COVID-19 vaccine", "CXCL10 gene", "CXCR3 gene", "Cells", "Cellular Immunity", "Cessation of life", "Defect", "Development", "Dimensions", "Disease", "Epithelial Cells", "Evolution", "Flow Cytometry", "Generations", "Genetic Transcription", "Hospitalization", "Human", "Humoral Immunities", "IL8 gene", "Immune", "Immune Evasion", "Immune response", "Immunity", "Immunization", "Individual", "Infection", "Inflammation", "Inflammatory", "Inflammatory Response", "Innate Immune Response", "Interferon Type I", "Interferons", "Interleukin-1 beta", "Interleukin-6", "Knockout Mice", "Lower respiratory tract structure", "Lung", "Macrophage", "Mediating", "Memory", "Mucosal Immunity", "Mucous Membrane", "Mus", "Mutation", "Nasal Epithelium", "Nasal cavity", "Nose", "Pathogenicity", "Play", "Research", "Respiratory System", "Role", "SARS-CoV-2 B.1.351", "SARS-CoV-2 antibody", "SARS-CoV-2 immunity", "SARS-CoV-2 infection", "SARS-CoV-2 variant", "Severity of illness", "Signal Transduction", "Site", "Structure of parenchyma of lung", "Systems Biology", "T cell infiltration", "T cell response", "T-Cell Depletion", "T-Lymphocyte", "T-Lymphocyte Epitopes", "TNF gene", "Testing", "Tissues", "Trachea", "Upper respiratory tract", "Vaccinated", "Vaccination", "Vaccines", "Variant", "Viral", "Viral Load result", "Virus", "Virus Replication", "antigen-specific T cells", "antiviral immunity", "breakthrough infection", "chemokine", "conditional knockout", "cytokine", "effector T cell", "endogenous pyrogen", "immune activation", "immunopathology", "monocyte", "mouse genetics", "mouse model", "mucosal vaccine", "neutralizing antibody", "novel", "novel vaccines", "pandemic disease", "post SARS-CoV-2 infection", "prevent", "programs", "recruit", "respiratory", "response", "response to injury", "transcriptomics", "transmission process", "viral transmission", "virus development" ], "approved": true } }, { "type": "Grant", "id": "15528", "attributes": { "award_id": "1R01DK139107-01A1", "title": "Identifying mechanisms by which metformin regulates T cell responses in obesity", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)" ], "program_reference_codes": [], "program_officials": [ { "id": 26970, "first_name": "RAJATAVA", "last_name": "Basu", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-20", "end_date": "2029-11-30", "award_amount": 655369, "principal_investigator": { "id": 29197, "first_name": "Nancie", "last_name": "MacIver", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 817, "ror": "", "name": "UNIV OF NORTH CAROLINA CHAPEL HILL", "address": "", "city": "", "state": "NC", "zip": "", "country": "United States", "approved": true }, "abstract": "Obesity is associated with chronic inflammation and an impaired immune response to infection from select viruses, including influenza and SARS-CoV-2, leading to increased morbidity and mortality. Many studies have demonstrated a critical role for CD4+ and CD8+ T cells in this setting, with primary and memory T cell responses to viral infection impaired in mice and humans with obesity. Given the high prevalence of obesity and viral infections with influenza and coronavirus worldwide, it is critically important to understand T cell dysfunction in obesity and identify novel strategies to improve T cell responses to infection in this high-risk population. T cell function and metabolism are closely linked, and many studies have demonstrated that changes to CD4+ and CD8+ T cell metabolism influence T cell fate and function. We have found that activated CD4+ T cells from obese mice have an altered metabolic profile characterized by increased glucose uptake and increased mitochondrial oxidation. This represents a unique cellular metabolic phenotype that may mechanistically explain obesity- associated T cell dysfunction. Interestingly, weight loss was unable to normalize adipose inflammation, reverse altered T cell metabolism, or improve the impaired immune response to influenza in obese mice. In contrast; systemic treatment of obese mice with metformin reversed CD4+ T cell metabolic dysfunction and improved survival following influenza infection. The clinical relevance and importance of this finding are supported by multiple observational and retrospective studies over the last few years showing that patients taking metformin have reduced disease severity and mortality to both influenza and COVID. Multiple lines of evidence point to a key role for metformin in regulating T cell immune responses. First, metformin has been found to alter the gut microbiome, which we know to influence both tissue-specific and systemic inflammation, and thereby influence T cells indirectly. Second, metformin has been shown to attenuate several inflammatory diseases by regulating the balance of regulatory and effector T cells. Third, we have generated preliminary data in our lab showing that metformin decreases oxidative metabolism, as well as the production of inflammatory cytokines in activated CD4+ and CD8+ T cells and differentiated Th1 and Th17 cells in vitro, indicating a direct effect of metformin on T cells. Therefore, the overall objective of this proposal is to elucidate the mechanisms by which metformin regulates T cell metabolism and function, directly and indirectly, using mouse models and human samples. To do so, we will perform the following aims: (1) Identify changes in gut microbiome and inflammatory cytokines in obese mice treated with metformin and determine if these changes drive T cell responses; (2) Determine the molecular mechanisms by which metformin directly affects T cell metabolism and function; and (3) Test if treatment with metformin can reverse obesity-associated dysfunction in human T cells. Successful completion of these aims will identify mechanisms by which metformin regulates T cell metabolism and function and reveal novel targets to improve treatment to viral infection in patients with obesity.", "keywords": [ "2019-nCoV", "Adenylate Cyclase", "Adipose tissue", "Affect", "Animals", "Attenuated", "Body Weight decreased", "CD4 Positive T Lymphocytes", "CD8-Positive T-Lymphocytes", "COVID-19", "Caloric Restriction", "Cell Physiology", "Cell Respiration", "Cell Separation", "Cells", "Cellular Metabolic Process", "Chronic", "Communicable Diseases", "Coronavirus", "Cryopreservation", "Cyclic AMP", "Data", "Diabetes Mellitus", "Disease", "Equilibrium", "Eragrostis", "Functional disorder", "Funding", "GTP-Binding Proteins", "High Prevalence", "Human", "Immune", "Immune response", "Impairment", "In Vitro", "Infection", "Inflammation", "Inflammatory", "Influenza", "Link", "Memory", "Metabolic dysfunction", "Metformin", "Mitochondria", "Molecular", "Monitor", "Morbidity - disease rate", "Mus", "Obese Mice", "Obesity", "Observational Study", "Outcome", "Patients", "Peripheral Blood Mononuclear Cell", "Pharmaceutical Preparations", "Production", "Purinergic P1 Receptors", "Receptor Signaling", "Recording of previous events", "Regulatory T-Lymphocyte", "Retrospective Studies", "Role", "Sampling", "Serum", "Severity of illness", "Signal Induction", "T cell response", "T memory cell", "T-Cell Activation", "T-Lymphocyte", "Testing", "Thinness", "Tissues", "United States National Institutes of Health", "Virus", "Virus Diseases", "Vulnerable Populations", "Weight", "bariatric surgery", "biobank", "clinically relevant", "cytokine", "drug discovery", "effector T cell", "fecal transplantation", "glucose uptake", "gut microbiome", "high risk population", "human subject", "improved", "influenza infection", "influenzavirus", "metabolic phenotype", "metabolic profile", "mortality", "mouse model", "novel", "novel strategies", "obese patients", "obese person", "obesity treatment", "oxidation", "pandemic influenza", "response", "seasonal influenza", "systemic inflammatory response" ], "approved": true } }, { "type": "Grant", "id": "15530", "attributes": { "award_id": "1R35NS137480-01", "title": "Epitranscriptomic regulation in the mammalian nervous system", "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": 22867, "first_name": "TIMOTHY M", "last_name": "LAVAUTE", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-23", "end_date": "2032-11-30", "award_amount": 985026, "principal_investigator": { "id": 12608, "first_name": "Guo-li", "last_name": "Ming", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 232, "ror": "https://ror.org/00b30xv10", "name": "University of Pennsylvania", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 232, "ror": "https://ror.org/00b30xv10", "name": "University of Pennsylvania", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "Epitranscriptomics, analogous to the epigenetic code formed by DNA and histone modifications, is the study of more than 170 chemically distinct types of RNA modifications, which modulate nearly all aspects of RNA metabolism, such as splicing, translocation, decay, stability, and translation. The recent profound success of COVID19 mRNA vaccines utilizing the pseudo-uridine modification highlights the translational potential of epitranscriptomics. Emerging evidence suggests diverse roles and mechanisms of dynamic RNA modifications in the mammalian nervous system and the association of epitranscriptomic dysregulations with developmental, neurological, psychiatric, and degenerative brain disorders. The majority of recent epitranscriptomic studies used cultured immortalized cell lines and the physiological functions of various RNA modifications remain largely unexplored. Recent technical advances in human induced pluripotent stem cell (iPSC)-derived brain organoids and genome editing open doors to investigate epitranscriptomic regulation in human brain development processes and associated brain disorders. The overarching goal of this research program is to investigate roles and mechanisms of epitranscriptomic regulation in the development and function of the mammalian nervous system, and pathological consequences of disrupting these processes, using both mouse and human iPSC-derived 2D and 3D brain organoid models. There are three interrelated projects designed to test innovative hypotheses and generate foundational data for the field. In Project 1, we will focus on the development of the hypothalamus, an understudied brain region that regulates many key physiological functions, such as sleep, reproduction, and feeding, through its distinct nuclei. Based on our preliminary finding of adult-onset obesity of mice with defective m6A signaling, we will test the hypothesis that m6A signaling regulates the fate specification of neural stem cells in the arcuate nucleus for generating feeding-related neurons both in mice and human arcuate organoids. In Project 2, we will use novel sequencing technology to reveal the landscape of locally translated transcripts at synapses and investigate the role of m6A signaling in regulating activity-dependent local translation of these transcripts at synapses in the mouse hippocampus and human hippocampal organoids. In Project 3, we will focus on several risk genes associated with microcephaly that encode writer proteins for diverse epitranscriptomic modifications beyond m6A. We will generate isogenic iPSC lines and genetically modified animal models to test the functional roles and mechanisms of these RNA modifications in cortical neurogenesis. Together, we will use several orthogonal approaches to investigate functional roles and mechanisms of neuroepitranscriptomics in regulating the mammalian nervous system and its causal roles in mediating some forms of developmental pathology. The research program will also provide a platform to train the next generation of scientists from diverse backgrounds at different career stages.", "keywords": [ "3-Dimensional", "Adult", "Animal Model", "Brain", "Brain Diseases", "Brain region", "COVID-19", "Cell Line", "Cell Nucleus", "Chemicals", "Code", "DNA Modification Process", "Data", "Development", "Epigenetic Process", "Genetically Modified Animals", "Goals", "Hippocampus", "Human", "Hypothalamic structure", "Mediating", "Microcephaly", "Modeling", "Modification", "Mus", "Nervous System", "Neurologic", "Neurons", "Obese Mice", "Organoids", "Pathologic", "Pathology", "Physiological", "Process", "Proteins", "Pseudouridine", "RNA", "RNA Splicing", "RNA metabolism", "RNA vaccine", "Regulation", "Reproduction", "Research", "Role", "Scientist", "Signal Transduction", "Sleep", "Specific qualifier value", "Structure of nucleus infundibularis hypothalami", "Synapses", "Testing", "Training", "Transcript", "Translating", "Translations", "career", "cell immortalization", "design", "epitranscriptomics", "feeding", "genome editing", "histone modification", "human induced pluripotent stem cells", "induced pluripotent stem cell", "innovation", "nerve stem cell", "neurogenesis", "next generation", "novel sequencing technology", "programs", "risk variant", "success", "translational potential" ], "approved": true } }, { "type": "Grant", "id": "15533", "attributes": { "award_id": "1R01AI186964-01", "title": "The role of cell, antigen, and antibody, in controlling virus infection through Fc-dependent mechanisms", "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": 29189, "first_name": "Moriah Jovita", "last_name": "Castleman", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-12-23", "end_date": "2029-11-30", "award_amount": 318085, "principal_investigator": { "id": 32074, "first_name": "Ceri", "last_name": "Fielding", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32075, "first_name": "Stephen", "last_name": "Graham", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, { "id": 32076, "first_name": "Jordan Scott", "last_name": "Orange", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, { "id": 32077, "first_name": "Richard", "last_name": "Stanton", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, { "id": 32078, "first_name": "Eddie Chung Yern", "last_name": "Wang", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, { "id": 32079, "first_name": "Michael", "last_name": "Weekes", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, { "id": 32080, "first_name": "Wioleta Milena", "last_name": "Zelek", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2549, "ror": "https://ror.org/03kk7td41", "name": "Cardiff University", "address": "", "city": "", "state": "", "zip": "", "country": "UNITED KINGDOM", "approved": true }, "abstract": "The ability of an�bodies to bind infected cells and ac�vate cellular immunity through an�body-dependent cellular cytotoxicity (ADCC), an�body-dependent cellular phagocytosis (ADCP), and complement-dependent cytolysis (CDC) is cri�cal to control of intracellular virus and intra-host dissemina�on. The induc�on of these responses is therefore highly desirable in an�viral and immunotherapeu�c responses. However, our understanding of how to exploit ADCC/ADCP/CDC significantly lags that of neutralising ac�vity. Whereas neutralising an�bodies can be readily induced by vaccina�on with entry glycoproteins or receptor-binding subdomains, it remains unclear how to select an�gens, domains, or epitopes, for op�mal ADCC ac�vity. We have shown that there is litle correla�on between the ability of an�bodies to neutralise and to ac�vate cellular immunity, and that previously unsuspected an�gens can induce significantly enhanced Fc-dependent ac�vity compared to those that induce neutralising responses. It is now cri�cal to understand why some an�gens and epitopes offer superior ac�va�on of cellular immunity. Our previous work required laborious wet-lab screening with ex vivo cells, virus infected cells, and proteomics, to iden�fy op�mal targets for this ac�vity. Deciphering the underlying biology of this process offers the poten�al to predict ideal an�gens and to design epitope-specific vaccina�on strategies, that maximise ADCC/ADCP/CDC responses in addi�on to neutralisa�on. This has the poten�al to enhance the efficacy of future vaccines and immunotherapies, as well as de-risk and accelerate their development. Fc-dependent immunity requires effector cell, an�body, epitope, and an�gen, to each co-ordinate. We therefore seek to understand how each of these aspects contributes to effec�ve control of intracellular virus. The molecular determinants that govern how NK cells control virus dissemina�on through ADCC will be assessed func�onally and through high- resolu�on imaging of the ADCC immunological synapse (IS), with proteomics used to determine why NK cells from different donors exhibit markedly different ADCC capaci�es. Molecular engineering of an�bodies will inves�gate the specificity requirements for ADCC responses, and methods of op�mising ADCC-inducing immunotherapies. Structural and IS-imaging studies will reveal how an�gen structure and epitope conforma�on affect ADCC efficacy, and whether the same requirements apply to the induc�on of ADCP and CDC. Finally, we will determine how predic�ons of Fc-dependent immunity can be rapidly validated. Although the way that these parameters interact is likely independent of any specific virus, viruses drama�cally remodel the infected cell surface to counteract host immunity and this can significantly alter the func�onal outcome of interac�ons. We will therefore use two different viruses throughout these studies – one which manipulates the surface proteome extensively (HCMV), and one less so (SARS-CoV-2) – to reveal whether virus immune-evasion impacts outcome, and whether any underlying principles are therefore virus-dependent. For both viruses we have iden�fied novel an�gens and monoclonals that provide enhanced ADCC responses as compared to current vaccine/immunotherapeu�c approaches.", "keywords": [ "2019-nCoV", "Acceleration", "Address", "Affect", "Ally", "Animal Model", "Antibodies", "Antigens", "Binding", "Biological Assay", "Biology", "Biophysics", "Cell surface", "Cell-Mediated Cytolysis", "Cells", "Cellular Immunity", "Complement", "Cytolysis", "Cytomegalovirus", "Data", "Development", "Disease", "Drama", "Effector Cell", "Engineering", "Epitopes", "Event", "Exhibits", "Fc Receptor", "Fc domain", "Future", "Glycoproteins", "Human", "Image", "Immune", "Immune Evasion", "Immunity", "Immunotherapy", "Knowledge", "Ligands", "Longevity", "Mediating", "Methods", "Molecular", "Natural Killer Cells", "Outcome", "Pathway interactions", "Persons", "Phagocytosis", "Phagocytosis Induction", "Process", "Proteins", "Proteome", "Proteomics", "Risk", "Role", "Specificity", "Structure", "Subunit Vaccines", "Surface", "Vaccines", "Viral", "Virus", "Virus Diseases", "Work", "assay development", "cell killing", "cell type", "design", "efficacy evaluation", "imaging study", "immunological synapse", "improved", "mutant", "novel", "pathogen", "receptor binding", "response", "screening", "single molecule", "tool", "tumor", "vaccine candidate", "vaccine development", "viral transmission" ], "approved": true } } ], "meta": { "pagination": { "page": 1385, "pages": 1397, "count": 13961 } } }