Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1384&sort=abstract
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=abstract", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1424&sort=abstract", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1385&sort=abstract", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1383&sort=abstract" }, "data": [ { "type": "Grant", "id": "7470", "attributes": { "award_id": "3R01AG063400-02S1", "title": "A Precision high content screening assay for AB-mediated neuronal cell cycle reentry", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Aging (NIA)" ], "program_reference_codes": [], "program_officials": [ { "id": 21115, "first_name": "LORENZO", "last_name": "REFOLO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2019-04-01", "end_date": "2022-01-31", "award_amount": 161500, "principal_investigator": { "id": 23269, "first_name": "ELIZABETH", "last_name": "SHARLOW", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 908, "ror": "https://ror.org/0153tk833", "name": "University of Virginia", "address": "", "city": "", "state": "VA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 908, "ror": "https://ror.org/0153tk833", "name": "University of Virginia", "address": "", "city": "", "state": "VA", "zip": "", "country": "United States", "approved": true }, "abstract": "We have established a human iPS-derived neuronal-glial cell model system that we are using to (1) study AβO-induced neuronal cell cycle reentry (CCR) as well as (2) screen for compounds that inhibit AβO-induced neuronal CCR. We now propose to adapt this cell-based model system to evaluate the effects on SARS-CoV-2 spike protein-ACE2 binding on neuronal “fitness”, responsiveness and intracellular signaling as well as use to screen for small molecule inhibitors that may used for the next generation SARS-CoV-2 therapeutics.", "keywords": [ "2019-nCoV", "Administrative Supplement", "Alzheimer&apos", "s Disease", "Amyloid", "Amyloid beta-42", "Amyloid beta-Protein", "Binding", "Binding Proteins", "Biological", "Biological Assay", "Biological Models", "Brain", "COVID-19", "Cell Cycle", "Cells", "Cessation of life", "Cleaved cell", "Data", "Development", "Distress", "End Point Assay", "Event", "FDA approved", "Failure", "Functional disorder", "Future", "Human", "Mediating", "Neuraxis", "Neuroglia", "Neuronal Dysfunction", "Neurons", "Patients", "Peptides", "Peptidyl-Dipeptidase A", "Pharmaceutical Preparations", "Pharmacodynamics", "Protein Isoforms", "Protein Subunits", "Proteins", "Reporting", "SARS coronavirus", "Signal Transduction", "Symptoms", "System", "Therapeutic", "Viral", "Viral Antigens", "Virus", "associated symptom", "base", "fitness", "induced pluripotent stem cell", "inhibitor/antagonist", "neuron loss", "neurotoxic", "neurotoxicity", "next generation", "prevent", "response", "screening", "small molecule inhibitor" ], "approved": true } }, { "type": "Grant", "id": "5569", "attributes": { "award_id": "3R01AI037562-24S1", "title": "Immunologic mechanisms that prevent autoimmunity", "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": 19319, "first_name": "Thomas R.", "last_name": "Esch", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-07-06", "end_date": "2023-01-31", "award_amount": 407798, "principal_investigator": { "id": 19320, "first_name": "HARVEY", "last_name": "CANTOR", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 997, "ror": "", "name": "DANA-FARBER CANCER INST", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "We have identified a subset of CD8+ cells programmed to inhibit activation and expansion of helper T (TH) cells through recognition of the class Ib MHC molecule Qa-1 (HLA-E in man). Mice that express a Qa-1 point mutation that disrupts binding of Qa-1 to the TCR/CD8 co-receptor of Treg develop dysregulated TFH responses and die of systemic autoimmune disease 9-12m after birth. Regulatory activity is mediated by <5% of CD8 T cells that express a diagnostic triad of surface receptors. We have also shown that the Helios transcription factor (TF) stabilizes the CD8 Treg genetic program and have recently identified the highly restricted T-cell receptor (TCR) repertoire that may mediate Ag-specific recognition by CD8 Treg. We use these findings to trace the development of this regulatory CD8 lineage and apply these insights towards development of novel therapeutic approaches to autoimmune disease. We propose here to test the premise that Qa-1-restricted CD8 Treg represent a unique regulatory lineage of CD8 cells that express a Helios-dependent genetic program and a restricted set of TCR specific for Qa-1/HA-E-associated self-peptides. In Aim 1, we will define the contribution of the TCR to intrathymic CD8 Treg selection and differentiation using Ag-specific TCR knock-in (KI) and retrogenic mice that express a TCR specific for Qa-1-restricted self-peptides. This analysis will also allow dissection of the molecular requirements for thymic selection and differentiation of class Ib MHC-dependent CD8+ Treg. Single-cell transcriptome analysis will be used to define the relationship between TCR specificity for Qa-1–peptide ligands and shaping of the lineage-specific genetic program of Ag-specific CD8 Treg. In Aim 2, we will define the contribution of the Helios TF to thymic and post-thymic differentiation of CD8 Treg. This approach will entail measurement of the impact of specific deletion of Helios at defined stages of Ag-specific CD8 Treg differentiation. The results from these studies and SA1 will provide a foundation for investigation of the interaction between Ag-specific CD8 Treg and target cells in disease settings (Aim 3). Here we will define the inhibitory interaction between Ag-specific CD8+ Treg and its target cells. Since Helios-dependent expression of NKG2D costimulatory receptors may be essential to CD8 Treg signaling, we will characterize the contribution of this costimulatory receptor to CD8 Treg activation by stress-associated Qa-1–Hsp60 and NKG2D ligands (NKG2D- L). Insight into this interaction will be applied to the design of nanoparticle-based therapeutic approaches to autoimmune disease.", "keywords": [ "Affect", "American", "Antigens", "Autoimmune", "Autoimmune Diseases", "Autoimmunity", "Binding", "Birth", "CD4 Positive T Lymphocytes", "CD44 gene", "CD8 receptor", "CD8-Positive T-Lymphocytes", "CD8B1 gene", "Cell Lineage", "Cells", "Cellular Stress", "Centers for Disease Control and Prevention (U.S.)", "ChIP-seq", "Child", "Chronic", "Clone Cells", "Cloning", "Complex", "Development", "Diagnostic", "Disease", "Disease Progression", "Disease model", "Dissection", "Elderly", "Elements", "Eragrostis", "Foundations", "Genes", "Genetic", "Heat shock proteins", "IL2RB gene", "Immunologics", "Infection", "Investigation", "Knock-in", "Knock-in Mouse", "Ligands", "Maintenance", "Measurement", "Mediating", "Modeling", "Molecular", "Molecular Analysis", "Mus", "Pathogenicity", "Pathway interactions", "Peptides", "Point Mutation", "Pre-Clinical Model", "Prevalence", "Property", "Qa-1 Antigen", "Regulatory Pathway", "Regulatory T-Lymphocyte", "Rheumatoid Arthritis", "Self Tolerance", "Shapes", "Signal Transduction", "Stress", "Surface", "T-Cell Antigen Receptor Specificity", "T-Cell Receptor", "T-Lymphocyte", "T-cell receptor repertoire", "Testing", "Tetanus Helper Peptide", "Therapeutic", "Thymus Gland", "Triad Acrylic Resin", "Up-Regulation", "autoreactivity", "base", "defined contribution", "design", "effector T cell", "insight", "long term memory", "man", "mouse model", "nanoparticle", "novel therapeutic intervention", "prevent", "programs", "receptor", "response", "systemic autoimmune disease", "transcription factor", "transcriptome" ], "approved": true } }, { "type": "Grant", "id": "6354", "attributes": { "award_id": "3R01AI037562-23S1", "title": "Immunologic mechanisms that prevent autoimmunity", "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": 21416, "first_name": "Thomas R.", "last_name": "Esch", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-07-06", "end_date": "2022-01-31", "award_amount": 366302, "principal_investigator": { "id": 21417, "first_name": "HARVEY", "last_name": "CANTOR", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 997, "ror": "", "name": "DANA-FARBER CANCER INST", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "We have identified a subset of CD8+ cells programmed to inhibit activation and expansion of helper T (TH) cells through recognition of the class Ib MHC molecule Qa-1 (HLA-E in man). Mice that express a Qa-1 point mutation that disrupts binding of Qa-1 to the TCR/CD8 co-receptor of Treg develop dysregulated TFH responses and die of systemic autoimmune disease 9-12m after birth. Regulatory activity is mediated by <5% of CD8 T cells that express a diagnostic triad of surface receptors. We have also shown that the Helios transcription factor (TF) stabilizes the CD8 Treg genetic program and have recently identified the highly restricted T-cell receptor (TCR)αβ repertoire that may mediate Ag-specific recognition by CD8 Treg. We use these findings to trace the development of this regulatory CD8 lineage and apply these insights towards development of novel therapeutic approaches to autoimmune disease. We propose here to test the premise that Qa-1-restricted CD8 Treg represent a unique regulatory lineage of CD8 cells that express a Helios-dependent genetic program and a restricted set of TCR specific for Qa-1/HA-E-associated self-peptides. In Aim 1, we will define the contribution of the TCR to intrathymic CD8 Treg selection and differentiation using Ag-specific TCR knock-in (KI) and retrogenic mice that express a TCR specific for Qa-1-restricted self-peptides. This analysis will also allow dissection of the molecular requirements for thymic selection and differentiation of class Ib MHC-dependent CD8+ Treg. Single-cell transcriptome analysis will be used to define the relationship between TCR specificity for Qa-1–peptide ligands and shaping of the lineage-specific genetic program of Ag-specific CD8 Treg. In Aim 2, we will define the contribution of the Helios TF to thymic and post-thymic differentiation of CD8 Treg. This approach will entail measurement of the impact of specific deletion of Helios at defined stages of Ag-specific CD8 Treg differentiation. The results from these studies and SA1 will provide a foundation for investigation of the interaction between Ag-specific CD8 Treg and target cells in disease settings (Aim 3). Here we will define the inhibitory interaction between Ag-specific CD8+ Treg and its target cells. Since Helios-dependent expression of NKG2D costimulatory receptors may be essential to CD8 Treg signaling, we will characterize the contribution of this costimulatory receptor to CD8 Treg activation by stress-associated Qa-1–Hsp60 and NKG2D ligands (NKG2D- L). Insight into this interaction will be applied to the design of nanoparticle-based therapeutic approaches to autoimmune disease.", "keywords": [ "Affect", "American", "Antigens", "Autoimmune Diseases", "Autoimmune Process", "Autoimmunity", "Binding", "Birth", "CD4 Positive T Lymphocytes", "CD44 gene", "CD8 receptor", "CD8-Positive T-Lymphocytes", "CD8B1 gene", "Cell Lineage", "Cells", "Cellular Stress", "Centers for Disease Control and Prevention (U.S.)", "ChIP-seq", "Child", "Chronic", "Clone Cells", "Cloning", "Complex", "Development", "Diagnostic", "Disease", "Disease Progression", "Disease model", "Dissection", "Elderly", "Elements", "Eragrostis", "Foundations", "Genes", "Genetic", "Heat shock proteins", "IL2RB gene", "Immunologics", "Infection", "Investigation", "Knock-in", "Knock-in Mouse", "Ligands", "Maintenance", "Measurement", "Mediating", "Modeling", "Molecular", "Molecular Analysis", "Mus", "Pathogenicity", "Pathway interactions", "Peptides", "Point Mutation", "Pre-Clinical Model", "Prevalence", "Property", "Qa-1 Antigen", "Regulatory Pathway", "Regulatory T-Lymphocyte", "Rheumatoid Arthritis", "Self Tolerance", "Shapes", "Signal Transduction", "Stress", "Surface", "T-Cell Antigen Receptor Specificity", "T-Cell Receptor", "T-Lymphocyte", "Testing", "Tetanus Helper Peptide", "Therapeutic", "Thymus Gland", "Triad Acrylic Resin", "Up-Regulation", "alpha-beta T-Cell Receptor", "autoreactivity", "base", "defined contribution", "design", "insight", "long term memory", "man", "mouse model", "nanoparticle", "novel therapeutic intervention", "prevent", "programs", "receptor", "response", "systemic autoimmune disease", "transcription factor", "transcriptome" ], "approved": true } }, { "type": "Grant", "id": "7794", "attributes": { "award_id": "1ZIABC011967-01", "title": "Deciphering the Double-Edged Role of IFITM3 during SARS-CoV-2 Infection", "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": [], "start_date": null, "end_date": null, "award_amount": 265660, "principal_investigator": { "id": 23608, "first_name": "Alex", "last_name": "Compton", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1601, "ror": "", "name": "DIVISION OF BASIC SCIENCES - NCI", "address": "", "city": "", "state": "", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1601, "ror": "", "name": "DIVISION OF BASIC SCIENCES - NCI", "address": "", "city": "", "state": "", "zip": "", "country": "United States", "approved": true }, "abstract": "We have successfully produced HIV-based pseudovirus bearing the spike protein of SARS-CoV-1 and SARS-CoV-2 and produced cell lines that are permissive to these pseudoviruses. We have developed a protocol for transiently transfecting human ACE2 (the receptor for SARS-CoV-1 and SARS-CoV-2) and TMPRSS2 (a protease that activates the fusion potential of SARS-CoV-1 and SARS-CoV-2 spike proteins) into HEK293T cells stably expressing human IFITM1, IFITM2, IFITM3, and mutants thereof. We have challenged these cells with the HIV-SARS pseudoviruses and found that the human IFITM proteins inhibit both SARS-CoV-1- and SARS-CoV-2-mediated entry into cells, albeit to different extents. Whereas IFITM3 strongly inhibits SARS-CoV-1-mediated entry, it only slightly inhibits that driven by SARS-CoV-2. Furthermore, if target cells express TMPRSS2, the inhibitory effect of IFITM3 is negligible. These results suggest that viruses utilizing TMPRSS2 have decreased sensitivity to IFITM proteins, indicating that TMPRSS2 usage may alter the virus entry route into the cell. Given this variable effect of ectopic IFITM protein expression, we assessed how IFITM proteins endogenously expressed in two cell lines that are naturally permissive to coronavirus infection (Caco-2 and Calu-3) affect pseudovirus infection. We found that siRNA-mediated knockdown of IFITM2 and IFITM3, but not IFITM1, led to enhanced infection by HIV-SARS-2 (about 3-fold). To complement our studies, we are collaborating with Jacob Yount at Ohio State University, who is challenging our cell lines with wild-type SARS-CoV-2.", "keywords": [ "2019-nCoV", "Affect", "Cell Culture Techniques", "Cell Line", "Cells", "Complement", "Coronavirus Infections", "Data", "Goals", "HIV", "HIV Infections", "Human", "IFITM1 gene", "Infection", "Influenza A virus", "Mediating", "Ohio", "Peptide Hydrolases", "Play", "Proteins", "Protocols documentation", "Research", "Role", "Route", "SARS coronavirus", "Severe Acute Respiratory Syndrome", "Severity of illness", "Small Interfering RNA", "TMPRSS2 gene", "Universities", "Virus", "base", "human coronavirus", "in vivo", "knock-down", "mutant", "novel coronavirus", "protein expression", "protein function", "receptor", "respiratory virus" ], "approved": true } }, { "type": "Grant", "id": "5692", "attributes": { "award_id": "3R01AI139633-04S1", "title": "Mechanisms of a Novel Combined Immunodeficiency Caused by a Homozygous Mutation in COPG1", "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": 19653, "first_name": "Deborah", "last_name": "Hodge", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-08-10", "end_date": "2023-04-30", "award_amount": 442500, "principal_investigator": { "id": 19654, "first_name": "RAIF SALIM", "last_name": "GEHA", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 798, "ror": "https://ror.org/00dvg7y05", "name": "Boston Children's Hospital", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "We identified a biallelic K652E mutation in the γ1-COP subunit of the heptameric coat protein I (COPI) complex in 5 Omani siblings, suffering from recurrent pulmonary infections with encapsulated bacteria, CMV and EBV viremia. The four older siblings presented with severe CD4+ T cell lymphopenia and increased T cell apoptosis; the youngest had normal T cell numbers shortly after birth, but developed CMV viremia and CD4+ T cell lymphopenia at 6 mo. Coat proteins deform membranes to generate transport vesicles. They also bind to cargo proteins to properly sort them into these vesicles, and ensure their transport to specific intracellular compartments. In the early secretory system, the COPII complex transports cargo from the endoplasmic reticulum (ER) to the Golgi, while the COPI complex transports select cargo in the other direction, from the Golgi to the ER, and additionally mediates CDC42-dependent transport through the Golgi. Specific sequences on cargo proteins recognized by COPI include the di-lysine and the di-arginine motifs. Coat proteins can also bind indirectly to COPI through transmembrane proteins that act as cargo receptors. These include the KDEL receptor (KDELR), which links COPI (residing on the cytosolic side of Golgi membrane) to soluble proteins within the Golgi (lumenal side) that have a KDEL sequence. KDEL proteins are abundant ER proteins involved in protein folding (chaperones). A fraction of KDEL proteins leak from the ER, and are retrieved from the Golgi to the ER through the KDELR and COPI. Defect in this retrieval leads to the loss of ER chaperones, which has been found to induce ER stress. Preliminary data show that fibroblasts from patients, and mice homozygous for the K652E γ1-COP mutation, express the mutant protein, but demonstrate defective COPI-mediated trafficking, and that the mutation disrupts the binding of the mutant COPI complex to KDELR. Mutant mice have severe hypogammaglobulinemia and poor antibody responses. Their B cells had increased ER stress and impaired immunoglobulin (Ig) secretion that was rescued by the ER stress inhibitor TUDCA. T cells from the mutant were normal in numbers, but had increased ER stress, and displayed increased apoptosis and diminished IL-4 production following sustained activation in vitro. We propose to test the hypothesis that the γ1-COP mutation disrupts COPI-mediated trafficking causing increased ER stress that impairs B and T cell function, increases susceptibility to bacterial and viral infection, and results in CD4+ T cell lymphopenia secondary to persistent viral infection. The studies proposed will elucidate the mechanisms by which a novel monogenic defect that impairs COPI-mediated trafficking leads to CID with CD4+ T cell lymphopenia, and will test pre-clinically the therapeutic efficacy of ER stress relieving drugs in this disease.", "keywords": [ "ADP-Ribosylation Factors", "Age", "Antibody Response", "Apoptosis", "Arginine", "B cell differentiation", "B-Lymphocytes", "Bacteria", "Bacterial Infections", "Binding", "Birth", "CD4 Positive T Lymphocytes", "CDC42 gene", "Capsid Proteins", "Cell Count", "Cell Survival", "Cell physiology", "Cells", "Coat Protein Complex I", "Complex", "Coupling", "Cytomegalovirus", "Cytosol", "Data", "Defect", "Disease", "Disease model", "Encapsulated", "Endoplasmic Reticulum", "Ensure", "Family", "Fibroblasts", "GTPase-Activating Proteins", "Golgi Apparatus", "Guanine Nucleotide Exchange Factors", "Guanosine Triphosphate Phosphohydrolases", "Human Herpesvirus 4", "Immunity", "Immunoglobulin G", "Immunoglobulins", "Immunologic Deficiency Syndromes", "Impairment", "In Vitro", "Integral Membrane Protein", "Interleukin-4", "KDEL receptor", "Link", "Lung infections", "Lymphocytic choriomeningitis virus", "Lymphopenia", "Lysine", "Mediating", "Membrane", "Molecular Chaperones", "Monomeric GTP-Binding Proteins", "Mus", "Mutant Strains Mice", "Mutation", "Outcome Study", "Patients", "Pharmaceutical Preparations", "Pneumococcal Infections", "Preclinical Testing", "Predisposition", "Production", "Proteins", "Recurrence", "Retrieval", "Role", "Secondary to", "Siblings", "Side", "System", "T-Lymphocyte", "Testing", "Transcript", "Treatment Efficacy", "Vesicle", "Viremia", "Virus Diseases", "chronic infection", "consanguineous family", "endoplasmic reticulum stress", "hypogammaglobulinemia", "in vivo", "inhibitor/antagonist", "lysyl-aspartyl-glutamyl-leucine", "man", "mutant", "mutant mouse model", "novel", "preclinical efficacy", "protein folding", "protein transport", "receptor", "receptor binding", "recruit", "response", "retrograde transport", "tauroursodeoxycholic acid", "trafficking", "vesicle transport" ], "approved": true } }, { "type": "Grant", "id": "5023", "attributes": { "award_id": "3R01AI139633-05S1", "title": "Mechanisms of a Novel Combined Immunodeficiency Caused by a Homozygous Mutation in COPG1", "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": 17985, "first_name": "Deborah", "last_name": "Hodge", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2018-05-03", "end_date": "2023-04-30", "award_amount": 52702, "principal_investigator": { "id": 17986, "first_name": "RAIF SALIM", "last_name": "GEHA", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 798, "ror": "https://ror.org/00dvg7y05", "name": "Boston Children's Hospital", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "We identified a biallelic K652E mutation in the γ1-COP subunit of the heptameric coat protein I (COPI) complex in 5 Omani siblings, suffering from recurrent pulmonary infections with encapsulated bacteria, CMV and EBV viremia. The four older siblings presented with severe CD4+ T cell lymphopenia and increased T cell apoptosis; the youngest had normal T cell numbers shortly after birth, but developed CMV viremia and CD4+ T cell lymphopenia at 6 mo. Coat proteins deform membranes to generate transport vesicles. They also bind to cargo proteins to properly sort them into these vesicles, and ensure their transport to specific intracellular compartments. In the early secretory system, the COPII complex transports cargo from the endoplasmic reticulum (ER) to the Golgi, while the COPI complex transports select cargo in the other direction, from the Golgi to the ER, and additionally mediates CDC42-dependent transport through the Golgi. Specific sequences on cargo proteins recognized by COPI include the di-lysine and the di-arginine motifs. Coat proteins can also bind indirectly to COPI through transmembrane proteins that act as cargo receptors. These include the KDEL receptor (KDELR), which links COPI (residing on the cytosolic side of Golgi membrane) to soluble proteins within the Golgi (lumenal side) that have a KDEL sequence. KDEL proteins are abundant ER proteins involved in protein folding (chaperones). A fraction of KDEL proteins leak from the ER, and are retrieved from the Golgi to the ER through the KDELR and COPI. Defect in this retrieval leads to the loss of ER chaperones, which has been found to induce ER stress. Preliminary data show that fibroblasts from patients, and mice homozygous for the K652E γ1-COP mutation, express the mutant protein, but demonstrate defective COPI-mediated trafficking, and that the mutation disrupts the binding of the mutant COPI complex to KDELR. Mutant mice have severe hypogammaglobulinemia and poor antibody responses. Their B cells had increased ER stress and impaired immunoglobulin (Ig) secretion that was rescued by the ER stress inhibitor TUDCA. T cells from the mutant were normal in numbers, but had increased ER stress, and displayed increased apoptosis and diminished IL-4 production following sustained activation in vitro. We propose to test the hypothesis that the γ1-COP mutation disrupts COPI-mediated trafficking causing increased ER stress that impairs B and T cell function, increases susceptibility to bacterial and viral infection, and results in CD4+ T cell lymphopenia secondary to persistent viral infection. The studies proposed will elucidate the mechanisms by which a novel monogenic defect that impairs COPI-mediated trafficking leads to CID with CD4+ T cell lymphopenia, and will test pre-clinically the therapeutic efficacy of ER stress relieving drugs in this disease.", "keywords": [ "ADP-Ribosylation Factors", "Age", "Antibody Response", "Apoptosis", "Arginine", "B cell differentiation", "B-Lymphocytes", "Bacteria", "Bacterial Infections", "Binding", "Birth", "CD4 Positive T Lymphocytes", "CDC42 gene", "Capsid Proteins", "Cell Count", "Cell Survival", "Cell physiology", "Cells", "Coat Protein Complex I", "Complex", "Coupling", "Cytomegalovirus", "Cytosol", "Data", "Defect", "Disease", "Disease model", "Encapsulated", "Endoplasmic Reticulum", "Ensure", "Family", "Fibroblasts", "GTPase-Activating Proteins", "Golgi Apparatus", "Guanine Nucleotide Exchange Factors", "Guanosine Triphosphate Phosphohydrolases", "Human Herpesvirus 4", "Immunity", "Immunoglobulin G", "Immunoglobulins", "Immunologic Deficiency Syndromes", "Impairment", "In Vitro", "Integral Membrane Protein", "Interleukin-4", "KDEL receptor", "Link", "Lung infections", "Lymphocytic choriomeningitis virus", "Lymphopenia", "Lysine", "Mediating", "Membrane", "Molecular Chaperones", "Monomeric GTP-Binding Proteins", "Mus", "Mutant Strains Mice", "Mutation", "Outcome Study", "Patients", "Pharmaceutical Preparations", "Pneumococcal Infections", "Preclinical Testing", "Predisposition", "Production", "Proteins", "Recurrence", "Retrieval", "Role", "Secondary to", "Siblings", "Side", "System", "T-Lymphocyte", "Testing", "Transcript", "Treatment Efficacy", "Vesicle", "Viremia", "Virus Diseases", "chronic infection", "consanguineous family", "endoplasmic reticulum stress", "hypogammaglobulinemia", "in vivo", "inhibitor/antagonist", "lysyl-aspartyl-glutamyl-leucine", "man", "mutant", "mutant mouse model", "novel", "preclinical efficacy", "protein folding", "protein transport", "receptor", "receptor binding", "recruit", "response", "retrograde transport", "tauroursodeoxycholic acid", "trafficking", "vesicle transport" ], "approved": true } }, { "type": "Grant", "id": "561", "attributes": { "award_id": "2041547", "title": "University-Industry Partnerships in the Social Sciences Helping Organizations Achieve Impact", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Social, Behavioral, and Economic Sciences (SBE)" ], "program_reference_codes": [], "program_officials": [ { "id": 1196, "first_name": "Tara", "last_name": "Behrend", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-09-01", "end_date": "2023-02-28", "award_amount": 58548, "principal_investigator": { "id": 1197, "first_name": "Ted", "last_name": "Knight", "orcid": null, "emails": "[email protected]", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 297, "ror": "https://ror.org/047s2c258", "name": "University of Maryland, College Park", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 297, "ror": "https://ror.org/047s2c258", "name": "University of Maryland, College Park", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "We live in a complex social world in which the challenges facing society evolve continuously, and organizations must adapt to meet them. With the rapid growth of social networks over the last two decades and the corresponding availability of big data, the behavioral and social sciences have become increasingly important to the development and growth of organizations’ capacity to understand and address global challenges. The recent COVID-19 pandemic has accentuated the importance of the social sciences in providing guidance during societal crises, particularly with respect to the successful operation of organizations during emergencies. Social, behavioral, and organizational science can help organizations address societal needs, and these contributions can be magnified through collaborations between academia and industry. With respect to such issues as shaping the future of work, harnessing data for societal benefit, supporting diversity and inclusion, advancing team science, establishing successful leadership and mentorship models within organizations, and understanding the impact of artificial intelligence on society, the social sciences are critical for advances and solutions. There are significant opportunities for expanding academic-corporate partnerships in the social sciences to help address urgent societal needs. The University of Maryland, College Park, in collaboration with the University Industry Demonstration Partnership, will host a three-day workshop in College Park, Maryland, convening a diverse group of experts and leaders from academia, industry, and government to consider how academic-corporate partnerships can advance social, behavioral, and organizational science research to positively impact science and society. This workshop will help generate more awareness about the collaborative opportunities that exist within the social, behavioral, economic, and organizational science disciplines, and will produce strategies to fuel future industry-university partnerships. The workshop will showcase research collaborations relevant to business practitioners, policy makers, and research communities, examine how organizations develop and operate successfully, especially amid current challenges such as the COVID-19 pandemic, and explore how university-industry collaborations in the social sciences can stimulate discovery, knowledge exchange, and economic development, helping to create value and achieve social impact.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "14049", "attributes": { "award_id": "2132730", "title": "EAGER: Discovering the hidden functional trait diversity of Bees (Apoidea) and predicting functional diversity impacts on rendered ecosystem services", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Biological Sciences (BIO)", "Population & Community Ecology" ], "program_reference_codes": [], "program_officials": [ { "id": 6665, "first_name": "Andrea", "last_name": "Porras-Alfaro", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-09-01", "end_date": null, "award_amount": 199957, "principal_investigator": { "id": 30558, "first_name": "Israel", "last_name": "Del Toro", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2397, "ror": "", "name": "LAWRENCE UNIVERSITY OF WISCONSIN", "address": "", "city": "", "state": "WI", "zip": "", "country": "United States", "approved": true }, "abstract": "We often associate pollination with a few external characteristics in bees (e.g., hairiness & tongue length) but bees are complex organisms with a plethora of unstudied morphological and physiological traits (e.g., gut structure, muscular form, and thermal tolerance) that can strongly influence their effectiveness as pollinators. This project will link unstudied, internal morphological traits with bee physiological responses. At its core this work links structure and function with the functional role of bees as pollinators. MicroCT technology will be used to render high-resolution quantitative imagery of internal morphological traits. Honeybees will be used as a model system and the work will be expanded to obtain imaging and an analytical framework of 50 species of wild bees across multiple groups. By linking morphology and physiology with functional diversity, this work has the potential to shape how we think about and manage pollinator biodiversity. This work will provide research and training opportunities to six undergraduate students that will work on microCT imaging techniques, biological data science and experimental biology on the physiology of bees. <br/><br/>This project will explore the associations between functional diversity and morphological and physiological traits that directly influence the ecosystem service of pollination provided by bees. The project uses microCT technology to image both honeybees and native wild bees over the course of two years. Specific emphasis is placed on internal morphological traits in relation to bee’s physiological responses (e.g., respiration and thermal tolerance) to environmental stress and thus ultimately impact a bee’s efficacy as a pollinator. The PI and undergraduate research assistants will conduct thermal tolerance and respiration assays on bees to determine potential links of functional trait morphology with important physiological responses. This work will provide workforce development opportunities.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "8333", "attributes": { "award_id": "1S10OD030286-01", "title": "Orbitrap Exploris 480 Basic System", "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": 11602, "first_name": "GUANGHU", "last_name": "Wang", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-05-15", "end_date": "2022-05-14", "award_amount": 600000, "principal_investigator": { "id": 24130, "first_name": "Simone", "last_name": "Sidoli", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 741, "ror": "https://ror.org/05cf8a891", "name": "Albert Einstein College of Medicine", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 741, "ror": "https://ror.org/05cf8a891", "name": "Albert Einstein College of Medicine", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "We present our proposal for the acquisition of a Thermo Scientific™ Orbitrap™ Exploris 480 mass spectrometer that would be installed in the Proteomics Core at the Albert Einstein College of Medicine. This instrument is critical for the performance of proteomics experiments by our NIH funded investigators. Specific projects presented in this proposal that will benefit enormously from this instrument include research on infectious diseases (herpes simplex virus, SARS-CoV2, Toxoplasma gondii, microsporidia, etc.), cancer (myelodysplastic syndrome, molecular regulation and targeting of pre-cancerous and cancer stem cells in hematopoiesis and leukemogenesis), aging (autophagy during aging, neurodegeneration), cardiovascular diseases and fundamental cell biology (obesity, mechanisms of cell death, chromatin, cell signaling). The Einstein Proteomics Core requires this instrument to replace a Thermo Scientific™ Orbitrap™ Velos. The Orbitrap Velos was acquired in 2010, and it has been the only proteomics-fitted instrument for the Core, but it now needs to be replaced as by the end of 2020 it will no longer be serviced by the vendor. The laboratory space of the proteomics facility has recently been completely renovated and Dr. Simone Sidoli was hired to lead proteomics research at Einstein. In the last year, the proteomics laboratory ran over 2,500 samples from approximately 50 different investigators' laboratories. The Einstein Proteomics Core is also a critical support service for the Einstein Cancer Center, the Nathan Shock Center for excellence on Biology of Aging Research (E-NSC) and the ERC-CFAR Einstein-Rockefeller-CUNY Center for AIDS research.", "keywords": [ "2019-nCoV", "Acquired Immunodeficiency Syndrome", "Aging", "Autophagocytosis", "Biology of Aging", "Cancer Center", "Cardiovascular Diseases", "Cell Death", "Cellular biology", "Chromatin", "Communicable Diseases", "Dysmyelopoietic Syndromes", "Funding", "Hematopoiesis", "Laboratories", "Lead", "Malignant Neoplasms", "Medicine", "Microsporidia", "Molecular", "Nerve Degeneration", "Obesity", "Performance", "Proteomics", "Regulation", "Research", "Research Personnel", "Sampling", "Services", "Shock", "Signal Transduction", "Simplexvirus", "System", "Toxoplasma gondii", "United States National Institutes of Health", "Vendor", "cancer stem cell", "college", "experimental study", "instrument", "leukemogenesis", "mass spectrometer", "premalignant" ], "approved": true } }, { "type": "Grant", "id": "7743", "attributes": { "award_id": "1ZIAAI000938-17", "title": "Paramyxoviruses as Vaccine Vectors Against Highly Pathogenic Viruses", "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": null, "end_date": null, "award_amount": 279642, "principal_investigator": { "id": 23540, "first_name": "Ursula", "last_name": "Buchholz", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1540, "ror": "https://ror.org/043z4tv69", "name": "National Institute of Allergy and Infectious Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1540, "ror": "https://ror.org/043z4tv69", "name": "National Institute of Allergy and Infectious Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "We previously constructed a first-generation construct called HPIV3-EbovZ GP, in which the complete genome of the JS strain of HPIV3 was modified by the addition of the EBOV GP gene in the third gene position, between the HPIV3 P and M genes. The JS strain is thought to be an attenuated HPIV3, based on previous clinical studies, although the basis of this attenuation is unknown. EBOV GP is the sole EBOV virion surface protein, the sole EBOV neutralization antigen, and the major protective antigen. The EBOV GP gene was engineered to have the appropriate HPIV3 transcription signals for it to be expressed as a separate mRNA by the HPIV3 polymerase. HPIV3-EbovZ GP was substantially immunogenic and protective when given to non-human primates by combined intranasal (IN) and intratracheal (IT) administration, even in animals previously infected with HPIV3. However, immunogenicity depended on IT delivery of vaccine: IN delivery alone was insufficient. This suggested that vector expression beyond the upper respiratory tract was necessary for immunogenicity. We therefore explored delivery of the HPIV3-EbovZ GP construct by the aerosol route in rhesus macaques. The aerosol route was generally more immunogenic and protective than the combined IN/IT route. This induced generally higher serum and mucosal EBOV-specific IgG, IgA, and neutralizing antibody titers, as well as EBOV-specific cellular responses in the lungs, including polyfunctional CD8+ T cells and CD4+ T helper cells that were predominately Th1. In addition, the HPIV3-EbovZ GP vaccine induced more robust cell-mediated and humoral immune responses than an alphavirus vaccine delivered parenterally in parallel. One aerosol dose of HPIV3-EbovZ GP conferred 100% protection to macaques against EBOV challenge. We developed a second-generation version of this vector, called HPIV3/delHNF/EbovZ-GP, in which the HPIV3 F and HN genes were deleted, leaving EBOV GP as the sole viral surface glycoprotein. A large comparative study in cynomolgus monkeys by our collaborator Alexander Bukreyev at the University of Texas Medical Branch, Galveston, (who made the construct while a Staff Scientist in LID/NIAID) showed that this second-generation version was even more protective than the first-generation even though it was very highly restricted for replication (much more restricted than the first-generation construct). We performed (with clinical collaborators at the Johns Hopkins Bloomberg School of Public Health) an open label phase 1 clinical trial to determine the safety, tolerability, and immunogenicity of HPIV3-EbovZ GP delivered IN in healthy adults in an inpatient setting (NCT025645750), which was intended to be a safety study prior to evaluating aerosol delivery. Ten subjects received two doses (4- to 8-week interval) of 6.0 log10 PFU of vaccine. The first dose was moderately infectious (7/10 subjects shed virus detected by qRT-PCR, mean peak titer 3.8 log10 genomic equivalents/ml, mean duration of shedding 7.9 days). Little shedding was detected after the second dose. A second cohort (n=20) received one of two planned doses of 7.0 log10 PFU of vaccine. Shedding was similar but of shorter duration (mean of 3.7 days). The vaccine was well tolerated, with the exception that asymptomatic ALT elevations were noted in 5 volunteers (3 mild, 2 moderate) in cohort 2 after vaccination and associated with shedding. All resolved by day 28. The study was halted due to these elevations of ALTs, but their significance is unclear. Because of this, this vaccine will not be administered further at this time. Induction of serum antibodies was poor (mucosal antibodies not yet analyzed), but this was expected since, as noted above, we had previously observed that administration by the IN route alone was poorly immunogenic in rhesus monkeys. We have initiated a Phase 1 study to evaluate the safety, infectivity, and immunogenicity of two doses of the HPIV3/HNF/EbovZ GP vaccine candidate when administered intranasally in healthy adults in an inpatient setting (NCT03462004). Participants are being enrolled sequentially in two cohorts. Participants in Cohort 1 have been randomly assigned to receive two doses of either 6.0 log10 PFU/mL of HPIV3/delHNF/EbovZ-GP vaccine or placebo. The first dose was given on Day 0 and the second dose was given 35 days later. Vaccine replication was evaluated by nasal wash and RT-qPCR and infectivity assays, and serum antibody responses will be measured. As expected, at the 6.0 log10 PFU dose, the HPIV3/HNF/EbovZ-GP vaccine was marginally infectious, and adverse events were generally mild to moderate. The study was deemed safe to proceed to the evaluation of the higher 7.0 log10 PFU dose after the closures due to the current SARS-CoV-2 pandemic will be lifted. Participants in Cohort 2 will be randomly assigned to receive two doses of either 7.0 log10PFU/mL of HPIV3/HNF/EbovZ-GP vaccine or placebo on Days 0 and 28.", "keywords": [ "2019-nCoV", "Adult", "Adverse event", "Aerosols", "Alphavirus", "Animals", "Antibodies", "Antibody Response", "Antibody titer measurement", "Antigens", "Attenuated", "Avian Influenza A Virus", "Avulavirus", "Biological Assay", "CD4 Positive T Lymphocytes", "CD8-Positive T-Lymphocytes", "Cattle", "Cavia", "Cell Culture Techniques", "Cells", "Child", "Chimera organism", "Clinical", "Clinical Research", "Comparative Study", "Coronavirus spike protein", "Development", "Dose", "Ebola virus", "Ebola virus envelope glycoprotein", "Effectiveness", "Engineering", "Enrollment", "Evaluation", "Family member", "Gene Order", "Generations", "Genes", "Genetic Transcription", "Genome", "Genomics", "Glycoproteins", "Human", "Immune response", "Immunity", "Immunoglobulin A", "Immunoglobulin G", "Infant", "Infection", "Influenza Hemagglutinin", "Inpatients", "Intranasal Administration", "Lifting", "Lung", "Macaca", "Macaca fascicularis", "Macaca mulatta", "Measures", "Mediating", "Medical", "Membrane Glycoproteins", "Membrane Proteins", "Messenger RNA", "Modification", "Mucosal Immunity", "Mucous Membrane", "National Institute of Allergy and Infectious Disease", "Newcastle disease virus", "Nose", "Para-Influenza Virus Type 1", "Para-Influenza Virus Type 3", "Paramyxovirus", "Participant", "Pathogenicity", "Phase I Clinical Trials", "Placebos", "Polymerase", "Population", "Primates", "Proteins", "Public Health Schools", "Quantitative Reverse Transcriptase PCR", "RNA", "Randomized", "Respiratory System", "Rodent", "Route", "SARS coronavirus", "Safety", "Scientist", "Serotyping", "Serum", "Severe Acute Respiratory Syndrome", "Signal Transduction", "Structure of respiratory epithelium", "Surface Antigens", "System", "TRIP10 gene", "Testing", "Texas", "Time", "United States National Institutes of Health", "Universities", "Upper respiratory tract", "Vaccination", "Vaccines", "Viral", "Viral Vaccines", "Virion", "Virus", "Virus Replication", "Virus Shedding", "Work", "attenuation", "base", "cohort", "conjunctiva", "design", "expression vector", "immunogenic", "immunogenicity", "neutralizing antibody", "nonhuman primate", "open label", "pandemic disease", "parainfluenza virus", "pathogen", "pathogenic virus", "phase 1 study", "respiratory", "response", "reverse genetics", "safety study", "seropositive", "tissue tropism", "vaccine candidate", "vaccine delivery", "vaccine development", "vector", "vecto" ], "approved": true } } ], "meta": { "pagination": { "page": 1384, "pages": 1424, "count": 14236 } } }