Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1391&sort=keywords
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=keywords", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1419&sort=keywords", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1392&sort=keywords", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1390&sort=keywords" }, "data": [ { "type": "Grant", "id": "8754", "attributes": { "award_id": "1R35GM143124-01", "title": "Mapping cellular communication at single-cell resolution through novel CRISPR systems", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 22244, "first_name": "MICHAEL", "last_name": "SAKALIAN", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-09-18", "end_date": "2026-08-31", "award_amount": 472500, "principal_investigator": { "id": 24547, "first_name": "Christof", "last_name": "Fellmann", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 917, "ror": "", "name": "J. DAVID GLADSTONE INSTITUTES", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 917, "ror": "", "name": "J. DAVID GLADSTONE INSTITUTES", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Mapping cellular communication at single-cell resolution through novel CRISPR systems The Fellmann lab focuses on decoding principles of cellular signaling in disease progression and therapy, and pioneering of CRISPR-Cas and RNA interference (RNAi) systems. For over a decade, my research has centered on better understanding RNA-guided immune systems and establishing innovative strategies to dissect disease, many of which have found broad application among the scientific community. My lab currently studies the interplay between Cas enzymes and DNA repair pathways to develop novel approaches for genome editing and precision medicine. We apply these quantitative, high-throughput methods to study the plasticity of signaling networks in health and disease, with the goal of translating insights into breakthrough therapies for patients. A persisting challenge in biology is recording molecular information in a cell-specific manner without disrupting the system under study. To overcome this, we propose transformative CRISPR platforms to track host-pathogen interactions and map pathway deregulation in human disease. The approaches rest on the development of Cas9 and guide RNA systems that are responsive to 1) pathogen-specific proteases (“ProCas9s”) or 2) mammalian cell-signaling events (“CRISPR-capture”), thereby enabling the recording of a cell’s history by inscribing marks at predetermined loci in the genome. As rapid response to emerging viral threats, we will develop a ProCas9 that can autonomously record SARS-CoV-2 infections and label respective cells. We will use this strategy to dissect long-term consequences of viral infection in cardiomyocytes. To enable general mapping of cellular communication, we propose a novel data recording methodology termed CRISPR-capture that places the expression of sgRNAs under the control of RNA polymerase II promoters, rather than the conventionally used RNA Pol-III promoters. Since mammalian signaling outputs are largely based on transcription factors regulating Pol-II promoters, CRISPR-capture tunes Cas activity to a cell’s state, providing the unique ability to map cellular signaling at single-cell resolution and monitor key biological events over the lifetime of a cell for the first time. Ultimately, we will leverage CRISPR-capture to monitor individual cells in four dimensions (space-time) during disease progression and treatment, to uncover organizational principles of tissue heterogeneity and establish new therapeutic strategies for patients. My multidisciplinary training in genome editing with Dr. Jennifer Doudna (University of California, Berkeley), functional genomics with Dr. Scott Lowe (Cold Spring Harbor Laboratory), and in-vivo animal models of human disease, allows me to bridge fundamental biology and patient-centered research. Moreover, my experience as co-founder and Chief Scientific Officer of a successful start-up company taught me invaluable lessons that will serve me well in directing and completing the proposed studies. Importantly, I am deeply committed to mentoring and serving as a role model for a talented and diverse group of next-generation scientists, and to providing equal opportunities to all.", "keywords": [ "Animal Model", "Biological", "Biology", "California", "Cardiac Myocytes", "Cells", "Clustered Regularly Interspaced Short Palindromic Repeats", "Communication", "Communities", "DNA Polymerase II", "DNA Polymerase III", "DNA Repair Pathway", "Data", "Development", "Disease", "Disease Progression", "Enzymes", "Event", "Four-dimensional", "Genome", "Goals", "Guide RNA", "Health", "Heterogeneity", "Human", "Immune system", "In Vitro", "Individual", "Label", "Laboratories", "Mammalian Cell", "Maps", "Mentors", "Methodology", "Methods", "Molecular", "Monitor", "Output", "Pathway interactions", "Patients", "Peptide Hydrolases", "RNA", "RNA Interference", "RNA Polymerase II", "Recording of previous events", "Research", "Resolution", "Rest", "SARS-CoV-2 infection", "Scientist", "Signal Transduction", "System", "Talents", "Time", "Tissues", "Training", "Translating", "Universities", "Viral", "Viral Physiology", "Virus Diseases", "base", "experience", "functional genomics", "genome editing", "human disease", "human model", "in vivo", "innovation", "insight", "multidisciplinary", "next generation", "novel", "novel strategies", "novel therapeutic intervention", "pathogen", "patient oriented", "precision medicine", "promoter", "response", "role model", "transcription factor" ], "approved": true } }, { "type": "Grant", "id": "10229", "attributes": { "award_id": "272201700041I-0-759302200001-1", "title": "Task A74: APP-High Throughput Evaluation of Therapeutics in Small Animal Models of Coronavirus Infection", "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": [], "start_date": "2022-06-30", "end_date": null, "award_amount": 1072875, "principal_investigator": { "id": 26181, "first_name": "JOHN", "last_name": "MORREY", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 375, "ror": "https://ror.org/00h6set76", "name": "Utah State University", "address": "", "city": "", "state": "UT", "zip": "", "country": "United States", "approved": true }, "abstract": "This contract provides for the development and standardization of small animal models of infectious diseases, and may include efficacy testing of candidate products, including GLP studies to support licensure.", "keywords": [ "Animal Model", "Contracts", "Coronavirus", "Coronavirus Infections", "Development", "Licensure", "Standardization", "Therapeutic Human Experimentation", "efficacy testing", "infectious disease model", "therapeutic evaluation" ], "approved": true } }, { "type": "Grant", "id": "8744", "attributes": { "award_id": "1C06OD032019-01", "title": "Establishment of the Bat Resource Center for the Study of Zoonotic Diseases", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "NIH Office of the Director" ], "program_reference_codes": [], "program_officials": [ { "id": 23882, "first_name": "CHARLES ASHLEY", "last_name": "Barnes", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-09-20", "end_date": "2026-05-31", "award_amount": 6748541, "principal_investigator": { "id": 24535, "first_name": "Gregory David", "last_name": "Ebel", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 323, "ror": "https://ror.org/03k1gpj17", "name": "Colorado State University", "address": "", "city": "", "state": "CO", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 323, "ror": "https://ror.org/03k1gpj17", "name": "Colorado State University", "address": "", "city": "", "state": "CO", "zip": "", "country": "United States", "approved": true }, "abstract": "This proposal outlines request to establish the Bat Resource Center for the Study of Zoonotic Diseases at Colorado State University. The Bat Resource Center is a $7.99M facility located adjacent to the Center for Vectorborne Disease and the Rocky Mountain Regional Biocontainment Laboratory. It is uniquely designed to be a vivarium with the necessary environmental and biosafety controls to successfully breed and maintain bats for use as animal models. This important animal model is critical to our understanding of viral pathogenesis and disease transmission as bats have been shown to be a reservoir for a number of human pathogens including the recent COVID-19 pandemic. The Bat Resource Center will greatly enhance our abilities to study these agents and will serve as a national resource for others using bat models.", "keywords": [ "Animal Model", "COVID-19 pandemic", "Chiroptera", "Colorado", "Disease", "Laboratories", "Modeling", "Resources", "Universities", "Vector-transmitted infectious disease", "Viral Pathogenesis", "Virus Diseases", "Zoonoses", "design", "disease transmission", "human pathogen" ], "approved": true } }, { "type": "Grant", "id": "7265", "attributes": { "award_id": "3R44TR002035-02S1", "title": "A computational platform to improve the prioritization of drugs and target genes for therapeutic intervention", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Center for Advancing Translational Sciences (NCATS)" ], "program_reference_codes": [], "program_officials": [ { "id": 11460, "first_name": "Lillianne M", "last_name": "Portilla", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-06-02", "end_date": "2020-06-30", "award_amount": 226800, "principal_investigator": { "id": 23060, "first_name": "Kriston Lyle", "last_name": "McGary", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1562, "ror": "", "name": "GENETIC NETWORKS, LLC", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1562, "ror": "", "name": "GENETIC NETWORKS, LLC", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true }, "abstract": "This project proposes further development of a computational discovery platform shown to quantifiably identify and prioritize both targets and compounds for therapeutic intervention, which will accelerate the development of newer, more effective drugs with fewer side-effects. This platform is based on a novel fusion of two state of the art computational approaches (phenolog mapping and functional networks) with proprietary data from Genetic Networks powerful gene-drug screening assays (H-Tech and Y-Tech) that identify drug targets, conserved drug target pathways, and off-target effects (e.g. toxicity) by genome- wide phenotypic profiling. The computational platform identifies conserved and functionally linked genes to define conserved biological modules, groups of gene that work tightly together and contribute to disease phenotypes and drug responses. The first aim is to improve the throughput and robustness of Genetic Networks computational platform to provide the pharmaceutical industry with a proven tool to select better compounds for their drug development pipelines and clinical trials. The second aim is to improve the prioritization of target genes that will be most effective in treating disease. Many genes have very similar copies, known as paralogs, which can complicate the interpretation of biological data. This project will integrate diverse biological information to prioritize the best gene target based on the disease, the relevant tissue, and how each gene interacts with other genes. The third aim is to identify common groups of genes involved in multiple disease and/or multiple drug responses. Understanding the genes involved in multiple biological processes allows pharmaceutical companies to repurpose already approved drug for new purposes and lowers the cost of developing multiple drugs for multiple disease. In addition, this approach will identify the potential drug interactions that can lead to severe side-effects when drugs are taken together without requiring animal testing or risking patient lives. This automated system will rapidly identify and prioritize therapeutic interventions across multiple diseases and will increase the success rate of drug discovery and provide guidance to repurpose existing drugs for new indications. Implementation of the platform described in this proposal will strengthen Genetic Networks' contributions to the goal of bringing new treatments to patients faster.", "keywords": [ "Animal Testing", "Area", "Biological", "Biological Assay", "Biological Process", "Client", "Clinical", "Clinical Trials", "Complement", "Computational algorithm", "Data", "Data Set", "Data Sources", "Databases", "Development", "Disease", "Drug Combinations", "Drug Industry", "Drug Interactions", "Drug Screening", "Drug Targeting", "Gene Targeting", "Genes", "Genetic", "Goals", "Gold", "Human", "Lead", "Licensing", "Link", "Lytic", "Manuals", "Orthologous Gene", "Pathway Analysis", "Pathway interactions", "Patients", "Pharmaceutical Preparations", "Pharmacologic Substance", "Phase", "Phenotype", "Quality Control", "Reporting", "Risk", "Specificity", "System", "Therapeutic", "Therapeutic Intervention", "Tissues", "Toxic effect", "Translating", "Validation", "Visualization", "Work", "Yeasts", "automated analysis", "base", "biological systems", "commercialization", "comorbidity", "computational platform", "cost", "data ingestion", "data pipeline", "data standards", "disease phenotype", "diverse data", "drug development", "drug discovery", "genome-wide", "human error", "improved", "novel", "paralogous gene", "prototype", "research and development", "response", "side effect", "success", "therapeutic target", "tool" ], "approved": true } }, { "type": "Grant", "id": "9157", "attributes": { "award_id": "1SC1AI155439-01", "title": "Targeting professional APCs using Fasciola hepatica FABP to suppresses inflammation", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 7788, "first_name": "Annette L.", "last_name": "Rothermel", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-08-01", "end_date": "2024-07-31", "award_amount": 360250, "principal_investigator": { "id": 24927, "first_name": "ANA M", "last_name": "ESPINO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1015, "ror": "", "name": "UNIVERSITY OF PUERTO RICO MED SCIENCES", "address": "", "city": "", "state": "PR", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1015, "ror": "", "name": "UNIVERSITY OF PUERTO RICO MED SCIENCES", "address": "", "city": "", "state": "PR", "zip": "", "country": "United States", "approved": true }, "abstract": "The growing use of `helminth-therapy' in the last decade to prevent or ameliorate inflammatory diseases is a promising and novel approach. Fasciola hepatica, one of the most globally prevalent parasitic helminths of domestic animals, is particularly adept at controlling the immune response of its host. At early stages of infection the parasite induces a dominant Th2/T-regulatory-type immune response coincidental with suppression of Th1 responses. Recent studies have demonstrated that F. hepatica infection attenuates the clinical signs of murine experimental autoimmune encephalomyelitis [1] and prevents the development of Type-1 diabetes in a non-obese diabetic mouse model [2]. However, the immunoregulation associated to F. hepatica lacks specificity and results in a compromised immune system unable to respond effectively to bystander infections [3, 4]. A better alternative for drug development would be to identify parasite molecules with immune-modulatory capacity and to characterize their precise mechanism of action. Fatty acid binding proteins (FABPs) are proteins that play an important role in the parasite's lipid metabolism and have been recently categorized as anti-oxidant molecules [5]. We have demonstrated that a recombinant 14.5kDa protein belonging to the fatty acid binding protein (Fh15) is able to significantly suppress the cytokine storm when is applied therapeutically 1h after exposure to lethal doses of LPS, which suggest that Fh15 could act as a TLR4-antagonist. Moreover, we also found that Fh15-treatment increased accumulation of large and small peritoneal MΦs (LPMs and SPMs) into the peritoneal cavity (PerC) compared to the of septic mice [6]. Moreover, we also demonstrated by proximity ligation assay (PLA) that the native F. hepatica FABP variant (Fh12) binds to the human CD14-coreceptor [7], which has been associated to the activation-signaling cascade of various TLRs [8-11]. Because TLR4 is directly involved in the inflammatory responses during sepsis and ulcerative colitis (UC), this role for Fh15 could have a significant impact on human health [12, 13]. Our central hypothesis is that the suppression of pro-inflammatory cytokines induced by injection (i.p.) with Fh15 is enough to prevent the high mortality in mice exposed to a lethal dose of LPS and to prevent or ameliorate the intestinal inflammation in a DSS-induced mouse model of UC. Both therapeutic effects will be directly associated with the production of M2-type MΦs in the PerC of animals and the induction of tolerogenic properties of DCs, which will be critically dependent on CD14. The proposed research is conceptually innovative because it is the first time that a protein of the F. hepatica FABP family, specifically Fh15, is investigated as an anti-inflammatory molecule and there are no reported works on MΦs and DCs in relation to Fh15 exposure in vivo or in vitro. Understanding how Fh15 modulate and interact with MΦs and DCs at early stages of innate immunity could contribute to the development of anti-inflammatory drugs against sepsis and other inflammatory diseases. The specific aims are: 1) Determine the capacity of Fh15 to suppress the pathologic effects of septic shock and ulcerous colitis (UC) in the mouse model and, 2) Determine whether Fh15 induces the tolerogenic properties of DCs and identify mechanism- underlying immunosuppression caused by Fh15. The proposed studies significantly will advance anti- inflammatory drug development based on helminth-antigen derived therapy by providing a well-defined F. hepatica molecule as drug target mechanism of action.", "keywords": [ "Animals", "Anti-Inflammatory Agents", "Antigen-Presenting Cells", "Antiinflammatory Effect", "Antioxidants", "Attenuated", "Binding", "Biological Assay", "CD14 gene", "CD4 Positive T Lymphocytes", "CD80 gene", "CD86 gene", "Cell Culture Techniques", "Cell surface", "Clinical", "Colitis", "Data", "Dendritic Cells", "Dendritic cell activation", "Development", "Dextrans", "Disease", "Docking", "Domestic Animals", "Dose", "Drug Targeting", "Endotoxemia", "Experimental Autoimmune Encephalomyelitis", "Exposure to", "FOXP3 gene", "Fasciola hepatica", "Fascioliasis", "Flow Cytometry", "Foundations", "Gene Proteins", "Genetic Transcription", "Goals", "Greater sac of peritoneum", "Health", "Helminth Antigens", "Helminths", "Hepatica", "Human", "IL2RA gene", "IL6 gene", "Immune", "Immune response", "Immune system", "Immunosuppression", "In Vitro", "Inbred NOD Mice", "Infection", "Inflammation", "Inflammatory", "Inflammatory Bowel Diseases", "Inflammatory Response", "Injections", "Insulin-Dependent Diabetes Mellitus", "Interleukin-1 beta", "Interleukin-10", "Knockout Mice", "Ligands", "Ligation", "Measures", "Medical", "Modeling", "Multiple Sclerosis", "Mus", "Myelogenous", "Natural Immunity", "Nature", "Parasites", "Parasitic infection", "Pathologic", "Peritoneal", "Pharmaceutical Preparations", "Play", "Population", "Production", "Property", "Protein Family", "Proteins", "Proteomics", "Recombinants", "Reporting", "Research", "Role", "Schistosomiasis", "Sepsis", "Septic Shock", "Serum", "Signal Pathway", "Signal Transduction", "Specificity", "Structure", "Symptoms", "TLR2 gene", "TLR4 gene", "TNFRSF5 gene", "Testing", "Therapeutic", "Therapeutic Effect", "Time", "Treatment Efficacy", "Ulcerative Colitis", "Variant", "Work", "animal tissue", "base", "chemokine", "chronic infection", "cytokine", "cytokine release syndrome", "drug development", "efficacy testing", "experimental study", "fatty acid-binding proteins", "helminth infection", "immunoregulation", "in vivo", "inflammatory disease of the intestine", "innovation", "lipid metabolism", "macrophage", "mortality", "mouse model", "novel", "novel strategies", "prevent", "response", "septic", "sodium sulfate", "synthetic polymer Bioplex", "vaccine candidate" ], "approved": true } }, { "type": "Grant", "id": "9158", "attributes": { "award_id": "5SC1AI155439-02", "title": "Targeting professional APCs using Fasciola hepatica FABP to suppresses inflammation", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 7788, "first_name": "Annette L.", "last_name": "Rothermel", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-08-01", "end_date": "2024-07-31", "award_amount": 360136, "principal_investigator": { "id": 24927, "first_name": "ANA M", "last_name": "ESPINO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1015, "ror": "", "name": "UNIVERSITY OF PUERTO RICO MED SCIENCES", "address": "", "city": "", "state": "PR", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1015, "ror": "", "name": "UNIVERSITY OF PUERTO RICO MED SCIENCES", "address": "", "city": "", "state": "PR", "zip": "", "country": "United States", "approved": true }, "abstract": "The growing use of `helminth-therapy' in the last decade to prevent or ameliorate inflammatory diseases is a promising and novel approach. Fasciola hepatica, one of the most globally prevalent parasitic helminths of domestic animals, is particularly adept at controlling the immune response of its host. At early stages of infection the parasite induces a dominant Th2/T-regulatory-type immune response coincidental with suppression of Th1 responses. Recent studies have demonstrated that F. hepatica infection attenuates the clinical signs of murine experimental autoimmune encephalomyelitis [1] and prevents the development of Type-1 diabetes in a non-obese diabetic mouse model [2]. However, the immunoregulation associated to F. hepatica lacks specificity and results in a compromised immune system unable to respond effectively to bystander infections [3, 4]. A better alternative for drug development would be to identify parasite molecules with immune-modulatory capacity and to characterize their precise mechanism of action. Fatty acid binding proteins (FABPs) are proteins that play an important role in the parasite's lipid metabolism and have been recently categorized as anti-oxidant molecules [5]. We have demonstrated that a recombinant 14.5kDa protein belonging to the fatty acid binding protein (Fh15) is able to significantly suppress the cytokine storm when is applied therapeutically 1h after exposure to lethal doses of LPS, which suggest that Fh15 could act as a TLR4-antagonist. Moreover, we also found that Fh15-treatment increased accumulation of large and small peritoneal MΦs (LPMs and SPMs) into the peritoneal cavity (PerC) compared to the of septic mice [6]. Moreover, we also demonstrated by proximity ligation assay (PLA) that the native F. hepatica FABP variant (Fh12) binds to the human CD14-coreceptor [7], which has been associated to the activation-signaling cascade of various TLRs [8-11]. Because TLR4 is directly involved in the inflammatory responses during sepsis and ulcerative colitis (UC), this role for Fh15 could have a significant impact on human health [12, 13]. Our central hypothesis is that the suppression of pro-inflammatory cytokines induced by injection (i.p.) with Fh15 is enough to prevent the high mortality in mice exposed to a lethal dose of LPS and to prevent or ameliorate the intestinal inflammation in a DSS-induced mouse model of UC. Both therapeutic effects will be directly associated with the production of M2-type MΦs in the PerC of animals and the induction of tolerogenic properties of DCs, which will be critically dependent on CD14. The proposed research is conceptually innovative because it is the first time that a protein of the F. hepatica FABP family, specifically Fh15, is investigated as an anti-inflammatory molecule and there are no reported works on MΦs and DCs in relation to Fh15 exposure in vivo or in vitro. Understanding how Fh15 modulate and interact with MΦs and DCs at early stages of innate immunity could contribute to the development of anti-inflammatory drugs against sepsis and other inflammatory diseases. The specific aims are: 1) Determine the capacity of Fh15 to suppress the pathologic effects of septic shock and ulcerous colitis (UC) in the mouse model and, 2) Determine whether Fh15 induces the tolerogenic properties of DCs and identify mechanism- underlying immunosuppression caused by Fh15. The proposed studies significantly will advance anti- inflammatory drug development based on helminth-antigen derived therapy by providing a well-defined F. hepatica molecule as drug target mechanism of action.", "keywords": [ "Animals", "Anti-Inflammatory Agents", "Antigen-Presenting Cells", "Antiinflammatory Effect", "Antioxidants", "Attenuated", "Binding", "Biological Assay", "CD14 gene", "CD4 Positive T Lymphocytes", "CD80 gene", "CD86 gene", "Cell Culture Techniques", "Cell surface", "Clinical", "Colitis", "Data", "Dendritic Cells", "Dendritic cell activation", "Development", "Dextrans", "Disease", "Docking", "Domestic Animals", "Dose", "Drug Targeting", "Endotoxemia", "Experimental Autoimmune Encephalomyelitis", "Exposure to", "FOXP3 gene", "Fasciola hepatica", "Fascioliasis", "Flow Cytometry", "Foundations", "Gene Proteins", "Genetic Transcription", "Goals", "Greater sac of peritoneum", "Health", "Helminth Antigens", "Helminths", "Hepatica", "Human", "IL2RA gene", "IL6 gene", "Immune", "Immune response", "Immune system", "Immunosuppression", "In Vitro", "Inbred NOD Mice", "Infection", "Inflammation", "Inflammatory", "Inflammatory Bowel Diseases", "Inflammatory Response", "Injections", "Insulin-Dependent Diabetes Mellitus", "Interleukin-1 beta", "Interleukin-10", "Knockout Mice", "Ligands", "Ligation", "Measures", "Medical", "Modeling", "Multiple Sclerosis", "Mus", "Myelogenous", "Natural Immunity", "Nature", "Parasites", "Parasitic infection", "Pathologic", "Peritoneal", "Pharmaceutical Preparations", "Play", "Population", "Production", "Property", "Protein Family", "Proteins", "Proteomics", "Recombinants", "Reporting", "Research", "Role", "Schistosomiasis", "Sepsis", "Septic Shock", "Serum", "Signal Pathway", "Signal Transduction", "Specificity", "Structure", "Symptoms", "TLR2 gene", "TLR4 gene", "TNFRSF5 gene", "Testing", "Therapeutic", "Therapeutic Effect", "Time", "Treatment Efficacy", "Ulcerative Colitis", "Variant", "Work", "animal tissue", "base", "chemokine", "chronic infection", "cytokine", "cytokine release syndrome", "drug development", "efficacy testing", "experimental study", "fatty acid-binding proteins", "helminth infection", "immunoregulation", "in vivo", "inflammatory disease of the intestine", "innovation", "lipid metabolism", "macrophage", "mortality", "mouse model", "novel", "novel strategies", "prevent", "response", "septic", "sodium sulfate", "synthetic polymer Bioplex", "vaccine candidate" ], "approved": true } }, { "type": "Grant", "id": "5890", "attributes": { "award_id": "3R01AI148784-02S1", "title": "Insight into the Ebola virus glycoprotein fusion mechanism gleaned from the 2013-2016 epidemic GP-A82V variant", "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": 20156, "first_name": "LESLEY CONRAD", "last_name": "Dupuy", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-01-01", "end_date": "2021-12-31", "award_amount": 27920, "principal_investigator": { "id": 20157, "first_name": "JEREMY", "last_name": "LUBAN", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 790, "ror": "", "name": "UNIV OF MASSACHUSETTS MED SCH WORCESTER", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "The 2013–2016 Ebola virus (EBOV) disease epidemic was orders of magnitude larger than any previous EBOV outbreak. Preliminary data indicate that GP-A82V, an EBOV glycoprotein mutant that came to dominate the outbreak, increases infectivity in human cells. To elucidate the mechanism by which GP-A82V increases infectivity, and to clarify its significance for Ebola virus replication and transmission, we have assembled a team that leverages NIAID resources at the IRF-Fort Detrick and the Genomic Center for Infectious Diseases at The Broad Institute. Aim 1 will be to investigate the mechanism by which GP-A82V increases virion fusogenicity. Computer modeling suggests that GP-A82V destabilizes glycoprotein conformation. Mutations engineered based on the models will be tested for effects on infectivity, the reorganization of critical interactions as determined by molecular dynamics simulations, conformational equilibrium as determined by smFRET, novel assays for GP fusion, Cryo-EM of GP trimers, and crystal complexes with the NPC1 C-loop. Aim 2 will be to assess the effect of GP-A82V in the context of the EBOV Makona variant on infectivity in human cells in vitro and in humanized mice. We will generate a reverse genetic system for the ancestral EBOV Makona lineage and test the effect of GP-A82V on this background. Replication of WT and GP-A82V will be compared in U20S cells, in human dendritic cells, and in a novel humanized mouse model where the effect of GP-A82V on virus sequence adaptation to specific tissue compartments will be assessed. From these experiments we expect to clarify the significance of GP-A82V for viral replication and transmission, taking into account the genetic background of the EBOV and the species-specific effects of GP-A82V. Aim 3 will be to examine the effect of GP-A82V on neutralizing antibodies. Preliminary data indicate that GP-A82V is relatively resistant to neutralization by particular antibodies. Using a panel of monoclonal antibodies targeting different parts of GP, we will determine whether neutralization resistance is a general property of GP-A82V, or if this trait is specific to antibodies targeting particular regions of GP. If differential neutralization is observed with particular antibodies, the effect of these on viral titer will be tested in the humanized mouse model. We will also determine whether GP-A82V alters neutralization sensitivity to convalescent sera from Guineans infected early or later in the outbreak, and from individuals treated at Emory University. From these studies we hope to determine whether the antibody response to EBOV was different depending on whether a person was infected with virus bearing GP-A82 or GP-A82V. If differences in neutralization titer correlate with virus genotype it would contribute to understanding the factors that determine survival in an infected individual or the efficiency of transmission to people who come into contact with infected body fluids. Finally, these studies will provide valuable experimental tools that will inform our studies on GP structure and function.", "keywords": [ "Animals", "Antibodies", "Antibody Response", "Biochemical", "Biological Assay", "Biophysics", "Body Fluids", "Cells", "Cleaved cell", "Complex", "Computer Models", "Cryoelectron Microscopy", "Crystallization", "Data", "Dendritic Cells", "Disease Outbreaks", "Ebola Hemorrhagic Fever", "Ebola virus", "Engineering", "Epidemic", "Epidemiologic Factors", "Equilibrium", "Fluorescence Resonance Energy Transfer", "Funding", "Genetic", "Genome", "Genomic Centers for Infectious Diseases", "Genotype", "Glean", "Glycoproteins", "Human", "Immunologics", "In Vitro", "Individual", "Infection", "Institutes", "Measurement", "Modeling", "Molecular Conformation", "Monoclonal Antibodies", "Mucous Membrane", "Mutagenesis", "Mutation", "NPC1 gene", "National Institute of Allergy and Infectious Disease", "Natural Killer Cells", "Pathogenesis", "Pathogenicity", "Persons", "Pharmaceutical Preparations", "Property", "Proteins", "Reporting", "Research Personnel", "Resistance", "Resources", "Structure", "System", "Testing", "Tissues", "Universities", "Variant", "Viral", "Viral Pathogenesis", "Virion", "Virus", "Virus Replication", "atomic interactions", "base", "experimental study", "glycoprotein structure", "humanized mouse", "insight", "molecular dynamics", "monomer", "mouse model", "mutant", "neutralizing antibody", "novel", "novel therapeutics", "reconstitution", "reverse genetics", "single molecule", "structural glycoprotein", "tissue tropism", "tool", "trait", "transmission process", "viral transmission" ], "approved": true } }, { "type": "Grant", "id": "7646", "attributes": { "award_id": "1ZIAHL006234-04", "title": "Bloc transmission of viruses and implications for viral dynamics", "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": [], "start_date": null, "end_date": null, "award_amount": 1927387, "principal_investigator": { "id": 23449, "first_name": "Nihal", "last_name": "Altan-Bonnet", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1602, "ror": "", "name": "NATIONAL HEART, LUNG, AND BLOOD INSTITUTE", "address": "", "city": "", "state": "", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1602, "ror": "", "name": "NATIONAL HEART, LUNG, AND BLOOD INSTITUTE", "address": "", "city": "", "state": "", "zip": "", "country": "United States", "approved": true }, "abstract": "Coronavirus Egress Research- lysosomal release of viruses: We have identified as novel egress pathway exploited by coronaviruses. We have found that these viruses use lysosomes to be transported out of the cell. In the process of using lysosomes these viruses disrupt lysosomal function. We have found that this leads to profound defects in cell physiology including antigen presentation and may lead to the observed clinical abnormalities. Other posotive strand virus egress research=- en block release of viruses in vesicles. We identified differences in the host immune responses (innate and adaptive) when infected by bloc transmission versus single particle transmission. In summary when cells are infected with high multiplicities of viral genomes we find that they can no longer distinguish among entering non-self RNA and self RNA molecules, leading to an overall suppression of the innate immune response. This is a completely unexpected finding and upends much of what we know about innate immune responses and self/non-self RNA recognition. This study is now being submitted. We also found profound differences in the adaptive immune responses, specifically the mucosal immune response in the mammary glands of mothers whose pups were infected with free viruses versus vesicle-contained viruses. We are preparing a manuscript on this study.", "keywords": [ "Animals", "Antigen Presentation", "Cell physiology", "Cells", "Clinical", "Coronavirus", "Defect", "Human", "Immune response", "In Vitro", "Innate Immune Response", "Lead", "Lysosomes", "Mammary gland", "Manuscripts", "Mothers", "Mucosal Immune Responses", "Pathway interactions", "Population", "Process", "RNA", "Research", "Vesicle", "Viral", "Viral Genome", "Virulence", "Virus", "adaptive immune response", "in vivo", "novel", "particle", "pup", "transmission process", "viral transmission" ], "approved": true } }, { "type": "Grant", "id": "11994", "attributes": { "award_id": "1R01HL166464-01A1", "title": "Hypothalamic BDNF-mTOR signaling promotes hypertension by increasing cardiovascular sensitivity to stress", "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": 24802, "first_name": "Youngsuk", "last_name": "Oh", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-07-21", "end_date": "2027-06-30", "award_amount": 602687, "principal_investigator": { "id": 27884, "first_name": "Benedek", "last_name": "Erdos", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 27885, "first_name": "Matthew C", "last_name": "Weston", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 1131, "ror": "", "name": "UNIVERSITY OF VERMONT & ST AGRIC COLLEGE", "address": "", "city": "", "state": "VT", "zip": "", "country": "United States", "approved": true }, "abstract": "Chronic psychological stressors, including work-related stress, poor socioeconomic status and social isolation — all heightened by recent Covid-19 lockdowns — are major risk factors for hypertension and cardiovascular disease. Stress-activated regulatory mechanisms that stimulate the sympathetic nervous system to elevate blood pressure and redistribute blood flow to vital organs have evolved as life-protecting measures. From an evolutionary perspective, enhancing cardiovascular responses through long-term sensitization of these mechanisms is advantageous to organisms subjected to repeated stressors. However, in modern society, where coping with stressful situations rarely requires marked elevations in blood pressure, these actions become detrimental, as repeated unnecessary overload of the cardiovascular system exerts irreversible cardiac, vascular, and renal damage. Accordingly, augmented cardiovascular sensitivity to stressors in young, normotensive individuals is strongly correlated with the risk of becoming hypertensive later in life. Our long-term goal is to investigate the central mechanisms that determine the magnitude of blood pressure elevations elicited by stress in order to identify novel anti-hypertensive therapeutic targets. Here, we propose to investigate a novel signaling cascade mediated by brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) in the paraventricular nucleus of the hypothalamus (PVN), a brain region that plays a key role in orchestrating neuroendocrine and cardiovascular stress responses. BDNF expression is upregulated in the PVN during stress in response to increased excitatory input and neuronal activity. We have previously shown that BDNF elicits important adaptive changes within the PVN to elevate sympathetic activity and blood pressure. Our preliminary data suggest that BDNF stimulates mTOR, as part of mTOR complex-1 (mTORC1) in PVN neurons, and mTORC1 can fundamentally change neuronal morphology and synaptic connectivity, resulting in elevated neuronal excitability to augment cardiovascular stress responses and promote hypertension. To test our hypothesis, we employ a comprehensive array of in vitro patch-clamp studies, neuronal morphology analysis, as well as in vivo experiments using viral vector-mediated genetic manipulation of BDNF and mTORC1 and telemetric monitoring of cardiovascular parameters in rats. In Aim 1, we test whether mTORC1 activation in the PVN elevates blood pressure, augments cardiovascular stress responses, and mediates hypertensive actions of BDNF. In Aim 2, we determine whether BDNF–mTORC1 signaling regulates structural and functional characteristics of PVN pre- sympathetic neurons, resulting in enhanced excitability. In Aim 3, we test whether inhibition of BDNF–mTORC1 prevents chronic stress-induced hypertension in borderline hypertensive rats. These studies have the potential to significantly advance the field by establishing the BDNF–mTORC1 axis as a highly important regulator of autonomic and cardiovascular function that determines the amplitude of blood pressure elevations during stress and elicits long-term adaptive mechanisms in the PVN that promote the development of hypertension.", "keywords": [ "Animals", "Antihypertensive Agents", "Blood Pressure", "Blood Vessels", "Blood flow", "Brain", "Brain region", "Brain-Derived Neurotrophic Factor", "COVID-19", "Cardiac", "Cardiovascular Diseases", "Cardiovascular Physiology", "Cardiovascular system", "Characteristics", "Chronic", "Chronic stress", "Complex", "Conscious", "Data", "Development", "Electrophysiology (science)", "Equilibrium", "FRAP1 gene", "Female", "Future", "Glutamates", "Goals", "Hypertension", "Hypothalamic structure", "Immunofluorescence Immunologic", "In Vitro", "Individual", "Life", "Measures", "Mediating", "Metabolic", "Modeling", "Modernization", "Monitor", "Morphology", "Neuronal Plasticity", "Neurons", "Neurosecretory Systems", "Organ", "Organism", "Output", "Pathway interactions", "Physiological", "Play", "Predisposition", "Psychological Stress", "Public Health", "Rattus", "Regulation", "Research", "Risk", "Risk Factors", "Role", "Signal Transduction", "Slice", "Social isolation", "Societies", "Socioeconomic Status", "Spinal", "Stimulus", "Stress", "Sympathetic Nervous System", "Synapses", "Synaptic Transmission", "Techniques", "Telemetry", "Testing", "Vertebral column", "Viral Vector", "Work", "acute stress", "biological adaptation to stress", "blood pressure elevation", "blood pressure reduction", "cardiovascular health", "cardiovascular risk factor", "clinically relevant", "coping", "density", "experimental study", "genetic manipulation", "hypertensive", "in vivo", "male", "multidisciplinary", "neural circuit", "neuronal cell body", "neuronal circuitry", "neuronal excitability", "neurotransmission", "new therapeutic target", "normotensive", "novel", "paraventricular nucleus", "patch clamp", "prevent", "psychologic", "psychological stressor", "renal damage", "response", "sensor", "stressor", "therapeutic target", "transmission process" ], "approved": true } }, { "type": "Grant", "id": "9720", "attributes": { "award_id": "1R01AI171426-01", "title": "Study of arenavirus assembly", "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": 7012, "first_name": "LESLEY CONRAD", "last_name": "Dupuy", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2022-07-20", "end_date": "2027-06-30", "award_amount": 560443, "principal_investigator": { "id": 25553, "first_name": "MING", "last_name": "LUO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 25554, "first_name": "Z Hong", "last_name": "ZHOU", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 964, "ror": "https://ror.org/03qt6ba18", "name": "Georgia State University", "address": "", "city": "", "state": "GA", "zip": "", "country": "United States", "approved": true }, "abstract": "The devastating impact on public health, global economy and social stability incurred by the COVID-19 pandemic in the last two years has highlighted the importance of basic research into zoonotic pathogens. This application describes structural and functional studies into the rodent-borne human pathogen lymphocytic choriomeningitis virus (LCMV), a member of the Arenaviridae family in the Bunyavirales order. Like other members of the same family, LCMV has a negative sense, bi-segmented genome consisting of a large (L) and a small (S) segment. The L segment encodes the RNA-dependent RNA polymerase (L RdRp) protein and the multi-functional matrix protein (Z). The S segment encodes the viral nucleoprotein (NP) and the glycoprotein (GP) precursor of the glycoprotein complex (GPC) that is later cleaved into a stable signal peptide (SSP), GP1, and GP2. In the virion, nucleocapsids of NP coated L and S segments associated with the L protein are copackaged through interactions with membrane-associated Z proteins, which also interact with GPs embedded in the membrane envelope. Although structures of individual proteins from AVs have been solved by x-ray crystallography or cryo electron microscopy (cryoEM), the architectural organization of these proteins in the virion and the assembly mechanism of NP and RNA into the nucleocapsid are poorly understood. We hypothesize that NP interacts with genomic RNA segments and L RdRp to form a nucleocapsid, which is recruited to GP-decorated membrane patches through Z for budding of virions. The proposed structural and functional studies aim to test this hypothesis of LCMV virion and nucleocapsid assembly with techniques just established by our team in the collaborative studies of vesicular stomatitis virus (VSV), another negative sense RNA virus. Specifically, cryo electron tomography (cryoET) will be used to reconstruct the first 3D model of the LCMV virion at molecular resolution and atomic models of individual proteins will be fitted into the virion tomogram to establish the architectural framework of the virion and to unveil molecular interactions among GP, Z, NP and L proteins (Aim 1). Near-atomic resolution with novel sub-particle reconstruction method will be used to image fully assembled nucleocapsids consisting of NP protein and genomic RNA segment to define the protein-RNA interactions at atomic details. The nucleocapsid structure will be used to guide sub-particle reconstruction workflow and be complemented by in situ structures of nucleocapsids from virions (Aim 2). In both Aims, structure-guided functional studies will be performed to test hypotheses of assembly mechanisms of LCMV nucleocapsid and virion. Structure-function relationship relevant to viral RNA synthesis will also be explored. Overall, the anticipated results will provide new insights into the mechanism of virion assembly and viral RNA synthesis, not only for LCMV but also for Arenaviruses in general. The proposed studies harness cutting-edge technologies in structural biology and will generate new knowledge of viral structures currently unavailable to any of Arenaviruses. As such, the innovative studies shall make unique contributions by accelerating discoveries of antiviral agents and vaccines to control future AV outbreaks.", "keywords": [ "Animals", "Antiviral Agents", "Architecture", "Arenavirus", "Basic Science", "Binding", "Binding Proteins", "Bunyavirales", "COVID-19 pandemic", "Cell membrane", "Cells", "Collaborations", "Complement", "Complex", "Cryo-electron tomography", "Cryoelectron Microscopy", "Crystallization", "Crystallography", "Data", "Density Gradient Centrifugation", "Deposition", "Disease Outbreaks", "Family", "Future", "GP2 gene", "GTPBP1 gene", "Genetic Transcription", "Genome", "Genomic Segment", "Glycoproteins", "Human", "Image", "In Situ", "Individual", "Joints", "Junin virus", "Knowledge", "Lassa virus", "Lymphocyte Function", "Lymphocytic choriomeningitis virus", "Measures", "Membrane", "Messenger RNA", "Methods", "Modeling", "Molecular", "Mutation", "Nucleocapsid", "Nucleoproteins", "Old World Arenaviruses", "Peptide Signal Sequences", "Pichinde virus", "Polymerase", "Proteins", "Public Health", "RNA", "RNA Sequences", "RNA Viruses", "RNA chemical synthesis", "RNA-Directed RNA Polymerase", "RNA-Protein Interaction", "Resolution", "Rodent", "Series", "Signal Transduction", "Structure", "Structure-Activity Relationship", "System", "Techniques", "Technology", "Testing", "Tomogram", "Ultracentrifugation", "Vaccines", "Vesicular stomatitis Indiana virus", "Viral", "Viral Hemorrhagic Fevers", "Viral Packaging", "Viral Proteins", "Virion", "Virus", "Virus Assembly", "X-Ray Crystallography", "Zoonoses", "base", "density", "design", "electron crystallography", "experimental study", "genomic RNA", "human pathogen", "image reconstruction", "innovation", "insight", "member", "novel", "novel strategies", "pandemic disease", "particle", "pathogen", "plasma protein Z", "prototype", "recombinant virus", "reconstruction", "recruit", "social", "structural biology", "three dimensional structure", "three-dimensional modeling", "vaccine development", "viral RNA" ], "approved": true } } ], "meta": { "pagination": { "page": 1391, "pages": 1419, "count": 14184 } } }