Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=3&sort=-other_investigators
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-other_investigators", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1392&sort=-other_investigators", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=4&sort=-other_investigators", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=2&sort=-other_investigators" }, "data": [ { "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": "15573", "attributes": { "award_id": "5R01HL168041-02", "title": "Targeted treatment of acute lung injury using isolated lung perfusion", "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": 22454, "first_name": "GUOFEI", "last_name": "Zhou", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-12-20", "end_date": "2027-11-30", "award_amount": 725955, "principal_investigator": { "id": 31466, "first_name": "Irving L.", "last_name": "Kron", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 31467, "first_name": "Victor E", "last_name": "Laubach", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, { "id": 32091, "first_name": "ZEQUAN", "last_name": "YANG", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 908, "ror": "https://ror.org/0153tk833", "name": "University of Virginia", "address": "", "city": "", "state": "VA", "zip": "", "country": "United States", "approved": true }, "abstract": "Acute lung injury in the form of acute respiratory distress syndrome (ARDS) or ischemia-reperfusion injury (IRI) after lung transplant remains a major clinical issue associated with high morbidity and mortality. Currently, no methods exist for targeted treatment and rapid rehabilitation of lungs affected by ARDS. The majority of treatment strategies remain supportive in nature and are associated with continued poor outcomes. We have demonstrated breakthrough methods for treatment or prevention of acute lung injury via normothermic perfusion of isolated lungs in the form of ex vivo lung perfusion (EVLP) for marginal donor lungs or in vivo lung perfusion (IVLP) for ARDS. IVLP combines the benefits of extracorporeal membrane oxygenation and EVLP to provide a platform upon which injured lungs can be treated in vivo with targeted therapies in an isolated fashion without the potential risks of systemic treatment. We have demonstrated the rehabilitative capacity of isolated lung perfusion with Steen solution whereby sepsis-induced ARDS as well as IRI of transplanted donation after circulatory death (DCD) lungs are attenuated. We have also demonstrated that Steen solution directly preserves pulmonary endothelial barrier function and that inhibition of Panx1 or TRPV4 channels attenuates lung IRI via endothelial barrier protection. Thus, this project will test the overall hypothesis that rehabilitation of injured lungs by isolated, normothermic perfusion with Steen solution can be augmented by Panx1- or TRPV4-targeted therapy aimed at preserving endothelial barrier function to attenuate vascular inflammation and improve lung function. We will test our hypothesis using porcine and murine models of IVLP and EVLP of lungs injured by ARDS or IRI in three specific aims. Aim 1 will determine if isolated perfusion with Steen solution will rehabilitate injured lungs and if inhibition of Panx1 or TRPV4 during perfusion will augment rehabilitation and endothelial barrier function. Aim 1A will use a porcine, LPS-induced ARDS model to determine if IVLP provides durable lung rehabilitation up to 24 hours after IVLP. Aim 1B will determine if IVLP rehabilitates lungs injured in a porcine model of gastric aspiration-induced ARDS. Aim 1C will determine if EVLP rehabilitates murine lungs injured by ARDS caused by SARS-CoV-2 infection. Aim 2 will use a porcine lung transplant model to determine if rehabilitation of DCD lungs by EVLP can be augmented by treatment with Panx1 or TRPV4 inhibitor for successful transplant. Aim 3 will use in vitro models of LPS-induced injury to determine protective mechanisms of Steen solution involving direct anti-inflammatory effects on alveolar-capillary barrier or leukocytes. Our recent studies demonstrate the potential of IVLP for the treatment of severe ARDS, representing a major paradigm shift in the management of ARDS. If successful, our proposed studies will define IVLP as a novel platform for targeted therapy of severe ARDS and will facilitate clinical translation.", "keywords": [ "2019-nCoV", "Acute Lung Injury", "Acute Respiratory Distress Syndrome", "Affect", "Alveolar", "Anti-Inflammatory Agents", "Antiinflammatory Effect", "Attenuated", "Blood capillaries", "COVID-19", "COVID-19 patient", "Calcium Channel", "Cessation of life", "Clinical", "Edema", "Endothelium", "Epithelial Cells", "Epithelium", "Extracorporeal Membrane Oxygenation", "Family suidae", "Functional disorder", "Future", "Histology", "Hour", "Infection", "Inflammation", "Injury", "Laboratories", "Left", "Leukocytes", "Lipopolysaccharides", "Lung", "Lung Transplantation", "Measures", "Mechanics", "Mediating", "Methods", "Modeling", "Morbidity - disease rate", "Mus", "Natural Immunity", "Nature", "Operative Surgical Procedures", "Outcome", "Oxidative Stress", "Perfusion", "Permeability", "Play", "Prevention", "Recovery", "Regional Perfusion", "Rehabilitation therapy", "Reperfusion Injury", "Reperfusion Therapy", "Reproducibility", "Risk", "Rodent", "Role", "SARS-CoV-2 infection", "Sepsis", "Signal Pathway", "Signal Transduction", "Stomach", "TLR4 gene", "Testing", "Therapeutic", "Tight Junctions", "Transplantation", "Vanilloid", "Vascular Endothelial Cell", "Vascular Endothelium", "Ventilator", "alveolar epithelium", "antagonist", "aspirate", "attenuation", "clinical translation", "experience", "improved", "in vitro Model", "in vivo", "in vivo Model", "inflammatory milieu", "inhibitor", "lung basal segment", "lung failure", "lung injury", "lung ischemia", "lung microvascular endothelial cells", "monolayer", "mortality", "mouse model", "novel", "pharmacologic", "porcine model", "preservation", "protective effect", "pulmonary function", "pulmonary rehabilitation", "receptor", "sepsis induced ARDS", "targeted delivery", "targeted treatment", "transplant model", "treatment strategy", "vascular inflammation" ], "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 } }, { "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 } }, { "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 } }, { "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 } }, { "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 } }, { "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 } }, { "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": "15529", "attributes": { "award_id": "1U01AI187057-01", "title": "Influenza Modeling of Correlates of Protection for Optimal Immune Dynamics and Evolution.", "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": "2024-12-24", "end_date": "2029-11-30", "award_amount": 1171832, "principal_investigator": { "id": 32070, "first_name": "Rafael A.", "last_name": "Medina Silva", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32071, "first_name": "Gene Brian", "last_name": "Tan", "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": "Despite its high impact worldwide due to its significant disease burden and mortality, we still do not fully understand the molecular basis of host immune responses that lead to optimal protection against Influenza virus disease. Recent evidence with pandemic viruses such as SARS-CoV-2 and the 2009 H1N1 Influenza, has shown that new improved correlates of protection are needed to inform and guide vaccine development beyond our reliance in the induction of neutralizing antibodies. We will leverage and mine all publicly available data and our extensive multi-Omic dataset already available for 280 influenza infected individuals from the CHILE cohort (Training cohort), which include severe and non-severe individuals, with diverse comorbidities and vaccination status. Through the expertise of the investigators of the FLU-CODE consortium, we will conduct complementary longitudinal Omic and immunological readouts of the innate, adaptive and humoral immunity, to develop sparse machine learning models and use deep-learning models to identify host immune response markers mechanistically implicated in immune protection. We hypothesize that the integration and modeling of longitudinal host innate and adaptive immune responses after natural influenza virus infection and vaccination assessed though systems biology, will allow the identification of early immune signatures associated with improved outcome. We will use Omic datasets obtained during acute infection (days 1-14), convalescence (days 15-30) and, through a follow-up longitudinal cohort (Test Cohort) we will analyze samples after recovery (at 3, 6 and 12 months). These will be combined with analyses of the metabolome, and the innate and the B- and CD4+ and CD8+ T-cell responses, as well as humoral effector antibody responses, to identify novel correlates of protection beyond neutralizing antibodies. We will integrate our datasets with publicly available Omic data to enrich our deep-learning models to identify candidates genes and pathways involved protective responses. We will use mouse model systems of severe and non-severe infection, and vaccination/challenged mouse models that recapitulate human disease and immune status, respectively, to validate in vivo the most prominent immunological features identified by our modeling approach. The data generated will be further integrated by our modeling approach, to further fine-tune the model and identify early signature/biomarkers of immune protection. Our systems biology approach will deconvolute the contribution of the different arms of the immune responses to uncover novel of correlates of protection and immune persistence. The datasets generated by the FLU-CODE consortium will provide an unprecedented detailed mechanistical assessment of host immune responses to inform the development of improved vaccines against IV disease.", "keywords": [ "2019-nCoV", "Acute", "Animals", "Antibody Response", "B-Lymphocytes", "Biological Markers", "Biological Models", "CD8-Positive T-Lymphocytes", "Candidate Disease Gene", "Cells", "Characteristics", "Clinical", "Code", "Computer Analysis", "Computer Models", "Convalescence", "Data", "Data Set", "Development", "Disease", "Disease Outcome", "Early identification", "Evolution", "Goals", "Human", "Humoral Immunities", "Immune", "Immune response", "Immunity", "Immunization", "Immunologic Markers", "Immunologic Memory", "Immunologics", "Immunology procedure", "Individual", "Infection", "Influenza", "Influenza A Virus H1N1 Subtype", "Innate Immune Response", "Longevity", "Longitudinal cohort", "Measures", "Metadata", "Methods", "Modeling", "Molecular", "Molecular Profiling", "Multiomic Data", "Mus", "Natural Immunity", "Outcome", "Participant", "Pathway interactions", "Phase", "Primary Infection", "Proteomics", "Recovery", "Research", "Research Personnel", "Role", "Sampling", "Severity of illness", "Shapes", "Specimen", "Symptoms", "Systems Biology", "T cell response", "T-Lymphocyte", "Testing", "Training", "Vaccination", "Vaccines", "Virus", "Virus Diseases", "acute infection", "adaptive immune response", "adaptive immunity", "arm", "burden of illness", "candidate identification", "cohort", "comorbidity", "data modeling", "deep learning model", "disease phenotype", "experimental study", "flu", "follow-up", "high dimensionality", "human disease", "human model", "immunological status", "improved", "improved outcome", "in vivo", "in vivo Model", "influenza infection", "influenzavirus", "longitudinal analysis", "machine learning model", "metabolome", "metabolomics", "mortality", "mouse model", "multimodality", "multiple omics", "neutralizing antibody", "novel", "pandemic virus", "response", "response biomarker", "therapeutic evaluation", "transcriptomics", "vaccination strategy", "vaccine development" ], "approved": true } } ], "meta": { "pagination": { "page": 3, "pages": 1392, "count": 13920 } } }