Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=4&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=1397&sort=-other_investigators", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=5&sort=-other_investigators", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=3&sort=-other_investigators" }, "data": [ { "type": "Grant", "id": "15630", "attributes": { "award_id": "1R01AI182308-01A1", "title": "Integrated Host/Microbe (IHM) Metagenomics of the Lower Airway to Diagnose PediatricRespiratory Infections, Identify Etiologic Pathogens, and Predict Outcomes", "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": 8282, "first_name": "Inka I", "last_name": "Sastalla", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-01-01", "end_date": "2029-12-31", "award_amount": 781129, "principal_investigator": { "id": 32132, "first_name": "Charles", "last_name": "Langelier", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32133, "first_name": "PETER M", "last_name": "MOURANI", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 768, "ror": "https://ror.org/043mz5j54", "name": "University of California, San Francisco", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Lower respiratory tract infection (LRTI) leads to more deaths each year than any other type of infection and disproportionately affects children. The past three years have seen record pediatric hospitalizations due to RSV, influenza, and SARS-CoV-2, highlighting the burden of LRTI in this vulnerable demographic. LRTI remains diagnostically challenging in children due to high rates of viral/bacterial co-infections, noninfectious syndromes that mimic LRTI, frequent incidental pathogen carriage, and the limitations of existing clinical diagnostics. As a result, accurate and timely LRTI diagnosis is difficult to achieve in pediatric critical care, leading to the inappropriate use of empirical antibiotics, the emergence of resistant pathogens, and adverse patient outcomes. Respiratory infections involve a dynamic relationship among three key features: pathogens, the airway microbiome, and the host immune response. However, existing clinical tests rely primarily on pathogen detection, limiting their diagnostic and prognostic utility. Our group has pioneered integrated host/microbe (IHM) metagenomic next generation sequencing (mNGS) methods that enable accurate, culture-independent LRTI diagnosis by simultaneously assessing all three key LRTI features from a single tracheal aspirate sample. Here, we propose a prospective, multicenter cohort study of 400 critically ill children with acute respiratory failure requiring mechanical ventilation that is designed to validate and extend the IHM diagnostic we developed. Aim 1 will independently validate the performance of our existing IHM LRTI diagnostic classifier in distinguishing LRTI from non-infectious acute respiratory conditions and in identifying likely etiologic pathogens. Aim 2 will develop a novel host gene expression classifier specifically for bacterial LRTI rule-out, which would reduce unnecessary antibiotic use in a principled manner. For both Aims 1 and 2, we will additionally develop parsimonious host-based PCR versions of the classifiers for rapid, point-of-care LRTI diagnosis and bacterial LRTI rule-out where mNGS capacity is unavailable. Finally, Aim 3 will develop novel IHM classifiers to predict LRTI outcomes, including prolonged mechanical ventilation and persistent acute respiratory distress syndrome (ARDS), which can facilitate prioritization of resources and intensive interventions to the highest-risk patients. This study promises to address the unmet need for accurate molecular LRTI diagnostics that detect emerging pathogens, enable judicious antimicrobial treatment, and predict outcomes in critically ill children. Our multidisciplinary team of translational scientists with experience in innovative metagenomic approaches is well- positioned to accomplish the study goals. The results of this study will directly inform the design of a future clinical trial evaluating the impact of IHM diagnostics on clinical management and patient outcomes.", "keywords": [ "2019-nCoV", "Acute", "Acute Respiratory Distress Syndrome", "Acute respiratory failure", "Address", "Affect", "Antibiotic Therapy", "Antibiotics", "Area Under Curve", "Bacterial Infections", "Biological Markers", "Biological Testing", "COVID-19 pandemic", "Cessation of life", "Child", "Childhood", "Clinical", "Clinical Management", "Clinical Trials", "Cohort Studies", "Communicable Diseases", "Critical Care", "Critically ill children", "Data", "Decision Making", "Detection", "Diagnosis", "Diagnostic", "Diagnostic tests", "Early identification", "Elements", "Enrollment", "Enterovirus", "Epidemiology", "Etiology", "Future", "Gene Expression", "Genetic Transcription", "Goals", "Hospitalization", "Immune response", "Infection", "Influenza", "Innovative Therapy", "Intervention", "Intubation", "Lower Respiratory Tract Infection", "Mechanical ventilation", "Medical center", "Medicine", "Metagenomics", "Methods", "Microbe", "Molecular", "Morbidity - disease rate", "Outcome", "Pathogen detection", "Patient-Focused Outcomes", "Patients", "Performance", "Positioning Attribute", "Preparation", "Prognosis", "Prospective cohort study", "Randomized Controlled Trials", "Reporting", "Resistance", "Resource Allocation", "Resources", "Respiratory Tract Infections", "Sampling", "Scientist", "Specimen", "Syndrome", "Testing", "Trachea", "Translational Research", "Validation", "Viral", "accurate diagnostics", "adjudication", "antimicrobial", "aspirate", "clinical application", "clinical care", "clinical diagnostics", "clinical investigation", "co-infection", "cohort", "design", "diagnostic assay", "diagnostic value", "emerging pathogen", "experience", "high risk", "improved", "infection management", "innovation", "lung microbiome", "machine learning method", "metagenomic sequencing", "microbial", "microbiome", "mortality", "multidisciplinary", "next generation sequencing", "novel", "novel diagnostics", "outcome prediction", "pathogen", "pathogenic microbe", "point of care", "prevent", "prognostic", "prognostic assays", "prognostic value", "prospective", "recruit", "respiratory", "respiratory microbiome", "respiratory pathogen", "secondary analysis", "success", "translational scientist" ], "approved": true } }, { "type": "Grant", "id": "15628", "attributes": { "award_id": "1R34MH134930-01A1", "title": "Building Healthy Eating and Self-Esteem Together for University Students (BEST-U): A Pilot Randomized Controlled Trial of an mHealth Intervention for Binge-Spectrum Disorders", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Mental Health (NIMH)" ], "program_reference_codes": [], "program_officials": [ { "id": 31611, "first_name": "Marcy Ellen", "last_name": "Burstein", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-01-01", "end_date": "2027-12-31", "award_amount": 249521, "principal_investigator": { "id": 32128, "first_name": "Kara Alise", "last_name": "Christensen Pacella", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32129, "first_name": "Kelsie Terese", "last_name": "Forbush", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 1496, "ror": "", "name": "UNIVERSITY OF KANSAS LAWRENCE", "address": "", "city": "", "state": "KS", "zip": "", "country": "United States", "approved": true }, "abstract": "Eating disorders (EDs) are a critical concern on college campuses. Moreover, since the COVID-19 pandemic, ED prevalence has increased by 62% in university women and 140% in university men. Resources are inadequate to meet demand, leading to delays in students’ access to treatment. Untreated (or poorly treated) EDs result in greater healthcare utilization and costs to students, as well as lower academic achievement and increased psychiatric disability and mortality, suggesting a critical need for quality ED treatment on university campuses and to rethink treatment delivery. One way to address this gap in care delivery is to improve treatment accessibility and scalability, such as dissemination via mobile apps. Guided self-help Cognitive- Behavior Therapy (CBT-gsh) is a cost-effective option that can be delivered by non-traditional service providers, such as nurses and physicians. Our scientific premise is that the mHealth CBT-gsh app, Building Healthy Eating and Self-Esteem Together for University Students (BEST-U), will lead to reductions in binge eating (primary outcome) through reductions in dietary restraint and weight/shape concerns (target mechanisms). Our pilot data showed strong support for our premise, specifically the need for brief, targeted mHealth interventions in students and the ability of the program to significantly reduce binge eating and impairment and increase wellbeing, with high user acceptability and low drop-out rates. However, prior to implementing BEST-U at other universities, we need to test the intervention in a real-world setting with the end goal of disseminating at scale. Our objectives are to: 1) conduct an effectiveness test of BEST-U compared to a similar dose of present-centered therapy (PCT) in students with non-low weight binge-spectrum EDs and 2) test target mechanisms that lead to changes in binge eating. To accomplish our objectives, we will test the following specific aims: 1) conduct an RCT of BEST-U (N=47) compared to a similar dose of PCT (N=47) in students with non-low weight binge-spectrum EDs; 2) test target mechanisms that lead to changes in binge eating and other ED symptoms; and 3) characterize barriers and facilitators to implementation across two campuses. Our exploratory aim will test food reinforcement and food-choice impulsivity as potential target mechanisms or response moderators of rapid response in binge eating. Given the rapidly rising rates of EDs and the lack of existing treatment resources, the proposed study is innovative and significant because it will provide a scalable treatment to fill gaps in care to promote student wellness and educational attainment. Our pilot data showed initial efficacy for BEST-U, yet the proposed study is necessary to validate the treatment in a student health setting prior to large-scale dissemination. Furthermore, given that few studies have identified underlying mechanisms that explain how CBT-gsh works and for whom, this study may lead to improved ability to tailor or modify existing CBT-gsh (e.g., personalized medicine approaches) or lead to novel intervention development for students who are unlikely to respond rapidly (or at all) to first-line CBT interventions for EDs.", "keywords": [ "Academic achievement", "Address", "Administrator", "Binge Eating", "COVID-19 pandemic", "Caring", "Clinical", "Clinical Services", "Cognitive Therapy", "Community Practice", "Data", "Disease", "Dose", "Dropout", "Eating", "Eating Disorders", "Education", "Effectiveness", "Effectiveness of Interventions", "Elements", "Emotions", "Ensure", "Focus Groups", "Food", "Frequencies", "Goals", "Health", "Health Care", "Health Personnel", "Health Services Accessibility", "Healthy Eating", "Impairment", "Impulsivity", "Intervention", "Lead", "Mental Health", "Mission", "Mobile Health Application", "Monitor", "National Institute of Mental Health", "Nurses", "Outcome", "Pattern", "Personal Satisfaction", "Physicians", "Population", "Postdoctoral Fellow", "Prevalence", "Prevention", "Professional counselor", "Psychological reinforcement", "Public Health", "Randomized", "Randomized Controlled Trials", "Reporting", "Research", "Resources", "Risk", "Shapes", "Student Health Services", "Students", "Symptoms", "Testing", "Theoretical Domains framework", "Training", "Treatment outcome", "United States National Institutes of Health", "Universities", "Weight", "Woman", "Work", "care delivery", "college", "cost", "cost effective", "dietary", "doctoral student", "effectiveness testing", "evidence base", "excessive exercise", "follow-up", "health administration", "health care service utilization", "health care settings", "implementation facilitators", "implementation framework", "implementation intervention", "implementation strategy", "improved", "innovation", "mHealth", "men", "mhealth interventions", "mobile application", "mortality", "multi-site trial", "novel", "personalized medicine", "practice setting", "primary outcome", "programs", "psychiatric disability", "psychologic", "purge", "response", "restraint", "secondary outcome", "self esteem", "self help", "service providers", "therapy development", "treatment arm", "university student" ], "approved": true } }, { "type": "Grant", "id": "15617", "attributes": { "award_id": "1R01AI189657-01", "title": "Synergistic Nanobodies for Pandemic Preparedness", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 6115, "first_name": "DIPANWITA", "last_name": "Basu", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-02-24", "end_date": "2030-01-31", "award_amount": 867563, "principal_investigator": { "id": 32114, "first_name": "JOHN D.", "last_name": "AITCHISON", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32115, "first_name": "MICHAEL P", "last_name": "ROUT", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 763, "ror": "https://ror.org/0420db125", "name": "Rockefeller University", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "Betacoronaviruses (beta-CoVs), including SARS-CoV-1, MERS-CoV, and SARS-CoV-2, have reshaped our understanding of pandemic preparedness. These viruses demonstrate a remarkable ability to mutate and evade defenses, continuing to infect populations worldwide despite extensive vaccination efforts and antiviral therapies. The chameleon-like nature of SARS-CoV-2, particularly its modifications to the Spike protein, consistently outpaces existing countermeasures, necessitating new strategies. This proposal introduces a pioneering class of nanobodies (Nbs), engineered from the immune system of llamas, designed to provide comprehensive protection against all beta-CoVs. These biologics not only advance treatment but also signify a pivotal step in pandemic preparedness, equipping us to outpace the relentless evolution of beta-CoVs. Our innovation lies in developing multivalent, synergistic combinations of broad-spectrum, high-efficacy Nbs. By harnessing these combinations, we amplify their efficacy and scope, concurrently increasing their resistance to viral mutations. Administered intranasally or directly to the lungs, these Nbs serve as both prophylactics and therapeutic agents. Our first Aim is to strategically expand upon our proven repertoires to identify, isolate, and characterize a much larger and more diverse repertoire of Nbs that collectively are strongly neutralizing across the beta-CoVs. We will use cutting-edge methods to produce diverse Nbs from llamas exposed to spike proteins of various beta- CoVs, selecting those with high affinity, specificity, and stability. We aim to discover synergistic, escape-resistant Nb pairs through combination testing and structural analysis. In our second Aim, we will optimize critical parameters important for developing broadly neutralizing Nb combinations and derivatives for human use. We will evaluate the in vivo synergistic potential of Nbs targeting major threats like MERS-CoV and SARS-CoV-2, and engineer Nbs to optimize their properties and efficacy in preparation for clinical trials. Deploying these pre- programmed Nbs at an outbreak's onset will protect first responders and medical personnel, reduce hospital surges, limit transmission, and buy time for new vaccine development and rollout. They will also provide crucial support to immunocompromised individuals, safeguarding the most vulnerable from the start. We hypothesize that our synergistic Nb combinations will introduce new beta-CoV neutralization methods, effectively prevent and treat infections, and maintain efficacy against emerging beta-CoV threats.", "keywords": [ "2019-nCoV", "Acceleration", "Affinity", "Anti-viral Therapy", "Antibodies", "Binding", "Biological Products", "Cells", "Clinical Trials", "Collaborations", "Development", "Disease Outbreaks", "Ensure", "Evolution", "Exhibits", "Exposure to", "Future", "Health Personnel", "Hospitals", "Human", "Immunocompromised Host", "Individual", "Infection", "Inhalators", "Intranasal Administration", "Llama", "Lung", "Membrane Glycoproteins", "Methods", "Middle East Respiratory Syndrome Coronavirus", "Modification", "Monoclonal Antibodies", "Mutate", "Mutation", "Nature", "Outcome", "Population", "Preparation", "Prevention", "Property", "Proteins", "Readiness", "Resistance", "SARS coronavirus", "SARS-CoV-2 variant", "Shapes", "Specificity", "Sum", "System", "Testing", "Therapeutic Agents", "Time", "Vaccination", "Variant", "Viral", "Virus", "betacoronavirus", "biophysical properties", "design", "first responder", "global health", "immunoengineering", "immunogenicity", "in vivo", "innovation", "insight", "nanobodies", "nanoengineering", "novel vaccines", "pandemic disease", "pandemic preparedness", "prevent", "prophylactic", "respiratory virus", "stem", "synergism", "transmission process", "vaccine development", "vaccine distribution" ], "approved": true } }, { "type": "Grant", "id": "15616", "attributes": { "award_id": "1R01AI185617-01A1", "title": "RNA epigenetic modifications in SARS-CoV-2", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 27781, "first_name": "Mary Katherine Bradford", "last_name": "Plimack", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-02-01", "end_date": "2030-01-31", "award_amount": 582618, "principal_investigator": { "id": 26224, "first_name": "Jianrong", "last_name": "Li", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32113, "first_name": "Mark E.", "last_name": "Peeples", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 778, "ror": "", "name": "OHIO STATE UNIVERSITY", "address": "", "city": "", "state": "OH", "zip": "", "country": "United States", "approved": true }, "abstract": "Post-transcriptional RNA modifications are widespread and regulates numerous biological processes including RNA metabolism, protein translation, gene expression, and disease. Among the more than 180 types of RNA modifications, N6-methyladenosine (m6A) and pseudouridine (Ψ) are the two most prevalent. The m6A modification is catalyzed by the host RNA methyltransferase complex of METTL3 and METTL14. The Ψ modification is converted from the nucleoside uridine (U) by the host pseudouridine synthases (PUSs). Despite being discovered in the 1950s, the biological functions of the m6A and Ψ modifications in the context of virus infection remain poorly understood. This project is built upon our recent development of high throughput sequencing techniques that have enabled mapping of m6A and ψ sites at a single base resolution. Using these techniques, we discovered that SARS-CoV-2 RNA isolated from well-differentiated primary human bronchial epithelial (HBE) cultures that include their in vivo target cells is heavily modified with m6A and ψ. In addition, we have found that depletion of several m6A and ψ writer proteins decreases SARS-CoV-2 replication in HBE culture. These findings led to our hypothesis that SARS-CoV-2 acquires m6A and Ψ modifications in its RNA to maximize virus replication. Thus, the goal of this project is to determine the mechanisms by which RNA m6A and ψ modifications modulate SARS-CoV-2 replication, gene expression, innate and adaptive immunity, and pathogenesis. In Aim 1, we will use a CRISP-Cas 9 technique to knock out host RNA m6A methyltransferases and PUSs in HBE cultures to determine the role(s) of m6A and Ψ modifications in the SARS-CoV-2 life cycle. We will also use knockout mice to examine the role(s) of m6A and Ψ modification in SARS-CoV-2 replication in vivo. We will also identify the specific PUS enzyme(s) that catalyze pseudouridylation on SARS-CoV-2 RNA. In Aim 2, we will mutate the m6A and/or ψ sites in the SARS-CoV-2 genomic RNA and use the reverse genetics system to generate recombinant SARS-CoV-2 lacking m6A and/or ψ modification sites and use them to determine the roles of m6A and ψ modifications on viral RNA metabolism, encapsidation, RNA replication, viral protein translation, and innate immunity. In Aim 3, we will determine whether m6A and ψ modifications modulate mucosal and adaptive immune responses of SARS-CoV-2 live attenuated vaccines (LAVs) and determine whether LAVs lacking m6A and/or ψ are more immunogenic in golden Syrian hamsters. Upon completion of this project, we expect to have unravelled the mechanisms by which m6A and Ψ modifications modulate the SARS- CoV-2 replication cycle, leading to the development of novel and improved LAVs and therapies for COVID-19 that target these RNA modifications.", "keywords": [ "2019-nCoV", "Adenosine", "Anti-viral Agents", "Anti-viral Therapy", "Antibodies", "Attenuated", "Attenuated Vaccines", "B-Lymphocytes", "Biological Process", "COVID-19", "COVID-19 treatment", "COVID-19 vaccine", "Carbon", "Cells", "Cessation of life", "Collaborations", "Complementary DNA", "Complex", "Development", "Disease", "Effectiveness", "Enzymes", "Epigenetic Process", "Exposure to", "Gene Expression", "Genetic Recombination", "Genetic Transcription", "Goals", "Hamsters", "High-Throughput Nucleotide Sequencing", "High-Throughput RNA Sequencing", "Human", "Immune response", "Infection", "Innate Immune Response", "Intramuscular", "Isomerism", "Knock-out", "Knockout Mice", "Life Cycle Stages", "Maps", "Mediating", "Mesocricetus auratus", "Methylation", "Methyltransferase", "Modeling", "Modification", "Mucosal Immune Responses", "Mucous Membrane", "Mutate", "Natural Immunity", "Nucleosides", "Nucleotides", "Pathogenesis", "Pharmaceutical Preparations", "Positioning Attribute", "Post-Transcriptional RNA Processing", "Process", "Proteins", "Pseudouridine", "Public Health", "RNA", "RNA Stability", "RNA metabolism", "RNA purification", "RNA replication", "Reader", "Recombinants", "Resolution", "Role", "Rotation", "SARS-CoV-2 immunity", "SARS-CoV-2 infection", "SARS-CoV-2 variant", "Signal Transduction", "Site", "Small Interfering RNA", "Societies", "System", "T-Lymphocyte", "Techniques", "Therapeutic Agents", "Translations", "Uridine", "Vaccines", "Viral Pathogenesis", "Viral Proteins", "Virus Diseases", "Virus Replication", "adaptive immune response", "adaptive immunity", "attenuation", "base", "bronchial epithelium", "genomic RNA", "immunogenic", "improved", "in vivo", "knock-down", "mRNA Translation", "novel", "novel therapeutics", "novel vaccines", "obligate intracellular parasite", "prevent", "public health relevance", "reverse genetics", "small hairpin RNA", "targeted treatment", "transmission process", "vaccine delivery", "variants of concern", "viral RNA" ], "approved": true } }, { "type": "Grant", "id": "15606", "attributes": { "award_id": "1R01HL171387-01A1", "title": "Analyzing effectiveness of ongoing natural experiments in telehealth", "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": 26847, "first_name": "ALISON GWENDOLYN MARY", "last_name": "Brown", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-03-01", "end_date": "2029-12-31", "award_amount": 705383, "principal_investigator": { "id": 32102, "first_name": "Mark J", "last_name": "Pletcher", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32103, "first_name": "Steven Michael", "last_name": "Smith", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 158, "ror": "https://ror.org/02y3ad647", "name": "University of Florida", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true }, "abstract": "Uncontrolled blood pressure (BP) is the most prevalent modifiable risk for cardiovascular disease (CVD) and disorders directly influencing CVD (e.g., diabetes, chronic kidney disease, etc.). Along with many other aspects of U.S. healthcare, management of uncontrolled BP was severely disrupted during the COVID- 19 pandemic. In response, many health systems rapidly accelerated implementation of new technologies, including telehealth visits for BP control and support for self-monitoring with home-based measurement of BP. Anecdotally, new BP control technologies and strategies have been implemented differentially with wide variation in timing and degree of utilization, but systematic analyses showing the extent and variability of implementation across sites are lacking. Meanwhile, substantial and variable backsliding in BP control rates across health systems was documented at the onset of the pandemic, and it is unclear how much of the variability is driven by differential implementation of new BP-related technologies and strategies. To learn from this unprecedented natural experiment and help guide the US healthcare enterprise towards more effective and equitable practices for management of BP control, we propose a mixed methods comparative effectiveness analysis. We will leverage our nationally scoped PCORnet Blood Pressure Control Laboratory (BPCL) – designed fundamentally for efficient surveillance of BP control and related process metrics using electronic health record (EHR) data – to develop and validate process metric queries that track implementation of new BP-related technologies & strategies, field these queries along with our previously developed metrics, extract trend results and individual patient-level data from participating sites, and conduct descriptive and causal inference analyses to decipher successful patterns of care for uncontrolled BP. And, we will conduct a positive deviance analysis with mixed methods approach to assess residual variability in BP control across clinics and learn from clinics with unexplained excellence. Our specific aims are to: 1) evaluate time trends and disparities in utilization of BP-related telehealth and home BP monitoring; 2) estimate causal effects of telehealth implementation on BP control and related metrics in hypertension management; and, 3) identify clinics with unexplained resilience in BP control and use mixed methods to analyze potential mechanisms and opportunities for dissemination of effective, scalable practices. As we have done in prior work, we will test for effect heterogeneity across important subgroups (sex, race, ethnicity) and place special emphasis on BP control in non-Hispanic Black patients, for whom disparities are historically largest. Findings from these aims will be discussed with stakeholders via webinar including a panel of frontline clinicians and leaders from positive deviant clinical sites, and disseminated via conference presentations and publications.", "keywords": [ "Abbreviations", "Acceleration", "Age", "American", "Blood Pressure", "COVID-19 pandemic", "Cardiovascular Diseases", "Caring", "Chronic Kidney Failure", "Clinic", "Code", "Consolidated Framework for Implementation Research", "Data", "Data Collection", "Diabetes Mellitus", "Disparity", "Effectiveness", "Electronic Health Record", "Equity", "Ethnic Origin", "Feedback", "Health Care", "Health system", "Heterogeneity", "Home", "Home Blood Pressure Monitoring", "Hypertension", "Interview", "Laboratories", "Learning", "Measurable", "Measurement", "Measures", "Methods", "Monitor", "Natural experiment", "Not Hispanic or Latino", "Outcome", "Outcomes Research", "Patient-Focused Outcomes", "Patients", "Patterns of Care", "Physiologic Monitoring", "Practice Management", "Process", "Publications", "Race", "Recommendation", "Residual state", "Rural", "Site", "Site Visit", "Standardization", "Subgroup", "Technology", "Testing", "Time trend", "Variant", "Visit", "Work", "black patient", "blood pressure control", "cardiovascular disorder risk", "clinical research site", "comparative effectiveness analysis", "data modeling", "design", "deviant", "health care settings", "hypertension control", "improved", "individual patient", "modifiable risk", "new technology", "novel strategies", "pandemic disease", "pandemic disruption", "partial recovery", "patient subsets", "pre-pandemic", "preventable death", "resilience", "response", "sex", "symposium", "technology validation", "telehealth", "trend", "webinar" ], "approved": true } }, { "type": "Grant", "id": "15599", "attributes": { "award_id": "1R01CA301643-01", "title": "Role of respiratory viral infections and inflammation in promoting metastatic outgrowth in the lung", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Cancer Institute (NCI)" ], "program_reference_codes": [], "program_officials": [ { "id": 21648, "first_name": "Elizabeth Lee", "last_name": "Read-Connole", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-03-01", "end_date": "2030-02-28", "award_amount": 672011, "principal_investigator": { "id": 32096, "first_name": "James V", "last_name": "Degregori", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32097, "first_name": "Mercedes", "last_name": "Rincon", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 784, "ror": "https://ror.org/02hh7en24", "name": "University of Colorado Denver", "address": "", "city": "", "state": "CO", "zip": "", "country": "United States", "approved": true }, "abstract": "The leading cause of breast cancer deaths is metastasis. Metastatic relapse can occur months to years after the initial diagnosis and treatment of the primary tumor. Cancer cells can disseminate from the primary tumor into different tissues including lungs and remain in a dormant state for years to decades. Awakening of these dormant disseminated cancer cells (DCC) leads to metastasis. Finding factors that trigger the awakening of dormant DCC and developing strategies to reduce the risk of awakening is therefore an unmet need. While it is known that inflammation is a key contributing factor to the awakening of dormant DCC, no studies have investigated whether inflammation triggered by viral respiratory infections (a very common infection worldwide) in the lung can promote the expansion of DCC and lead to the development of metastases. Our recent studies using a mouse model of breast cancer DCC dormancy in the lung have revealed a dramatic increase in DCC awakening and expansion in the lungs following influenza virus infection. Our data support the hypothesis that respiratory viral infections can promote DCC awakening and expansion through two phases: first, through IL-6 dependent DCC awakening and expansion, and second, CD4 T-cell mediated protection from elimination (in part by CD8 cells). We further show that infection with a mouse-adapted SARS-CoV-2 promotes a similar awakening and expansion of DCC in mice. Finally, epidemiological studies reveal how prior infection with SARS-CoV-2 infection increases metastatic progression in lungs and cancer- related deaths for cancer survivors. We propose to determine mechanisms by which acute respiratory viral infections induce the awakening of dormant DCC leading to metastatic disease, whether and how such infections can prime DCC for activation by subsequent exposures, and how CD4 and CD8 cells differentially control the persistence of expanded DCC during influenza virus infection. Impact: Proposed studies to understand how different pulmonary viral infections alter DCC dormancy and host immune responses, to determine the consequences for progression to metastatic disease, and to explore underlying mechanisms, should yield valuable and actionable insight into the key cell types and molecular mediators, informing early detection and prevention strategies for at-risk individuals.", "keywords": [ "2019-nCoV", "Acute", "Affect", "B-Lymphocytes", "Biological Markers", "Breast", "Breast Cancer Model", "Bronchus-Associated Lymphoid Tissue", "CD4 Positive T Lymphocytes", "CD8-Positive T-Lymphocytes", "COVID-19", "COVID-19 pandemic", "Cancer Patient", "Cancer Survivor", "Cells", "Cessation of life", "Data", "Development", "Diagnosis", "Disease", "Early Diagnosis", "Epidemic", "Epithelial Cells", "Genetic Transcription", "IL6 gene", "Immune", "Immune response", "Individual", "Infection", "Inflammation", "Inflammatory", "Influenza", "Interleukin-6", "Intervention", "Link", "Lung", "Lung infections", "Lymphocytic choriomeningitis virus", "Lymphoid Tissue", "Maintenance", "Malignant Breast Neoplasm", "Malignant Neoplasms", "Malignant neoplasm of lung", "Mediating", "Mediator", "Mesenchymal", "Metastatic Neoplasm to the Lung", "Metastatic/Recurrent", "Modeling", "Molecular", "Mus", "Neoplasm Metastasis", "Pathway interactions", "Persons", "Phase", "Phenotype", "Prevalence", "Prevention strategy", "Primary Neoplasm", "Proliferating", "Relapse", "Research", "Respiratory Tract Infections", "Risk", "Risk Reduction", "Role", "SARS-CoV-2 infection", "Seasons", "Signal Pathway", "Signal Transduction", "Source", "Testing", "Tissues", "Upregulation", "Viral", "Viral Respiratory Tract Infection", "Virus", "Virus Diseases", "cancer cell", "cell type", "cigarette smoking", "cytokine", "epidemiology study", "experience", "influenza infection", "influenzavirus", "insight", "mouse model", "pandemic disease", "prevent", "programs", "progression risk", "respiratory", "response", "risk mitigation", "seasonal influenza" ], "approved": true } }, { "type": "Grant", "id": "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 } } ], "meta": { "pagination": { "page": 4, "pages": 1397, "count": 13961 } } }