Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=3&sort=start_date
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=start_date", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1392&sort=start_date", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=4&sort=start_date", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=2&sort=start_date" }, "data": [ { "type": "Grant", "id": "7697", "attributes": { "award_id": "1ZIAAI001306-01", "title": "tissue tropism of coronavirus", "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": 41824, "principal_investigator": { "id": 23492, "first_name": "Yasmine", "last_name": "Belkaid", "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": "The COVID-19 condition caused by the novel coronavirus SARS-CoV-2 is an active, existential global health threat. A substantial fraction of those infected exhibit no symptoms, while others progress to severe illness resulting in multi-organ failure and death. The factors dictating whether an infected subject will progress to develop symptoms or will experience asymptomatic infection remains poorly understood. Using experimental models, work that we and others have conducted over the past few years revealed that the ability of a given microbe to cause disease can be highly contextual. Indeed, numerous factors can contribute to pathogen-induced morbidity or mortality including age, microbiota, nutritional status as well as co-infection or previous infections. Our combined laboratories have pioneered the development of murine models of infectious diseases and developed novel tools to track microbial tropism, tissue specific pathologies and immune responses to pathogens. Using models of murine coronavirus infection, this proposal aims at addressing the circumstances controlling anti-viral immunity and pathogenicity.", "keywords": [ "Acute", "Address", "Age", "COVID-19", "Cessation of life", "Coronavirus", "Coronavirus Infections", "Development", "Disease", "Exhibits", "Experimental Models", "Failure", "Family", "Goals", "Immune response", "Immunity", "Infection", "Intestines", "Intranasal Administration", "Laboratories", "Lung", "Microbe", "Modeling", "Morbidity - disease rate", "Murine hepatitis virus", "Mus", "Nutritional status", "Organ", "Pathogenicity", "Pathology", "Pulmonary Inflammation", "RNA Viruses", "Research Personnel", "Respiratory Signs and Symptoms", "Symptoms", "Tissues", "Tropism", "Virus", "Work", "antiviral immunity", "co-infection", "experience", "global health", "human disease", "infectious disease model", "member", "microbial", "microbiota", "mortality", "mouse model", "novel", "novel coronavirus", "nutrition", "pathogen", "tissue tropism", "tool" ], "approved": true } }, { "type": "Grant", "id": "7689", "attributes": { "award_id": "1ZIADK075023-12", "title": "Structural study of the HIV1 gp41 coat protein", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 995227, "principal_investigator": { "id": 23487, "first_name": "Adriaan", "last_name": "Bax", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1600, "ror": "https://ror.org/00adh9b73", "name": "National Institute of Diabetes and Digestive and Kidney Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1600, "ror": "https://ror.org/00adh9b73", "name": "National Institute of Diabetes and Digestive and Kidney Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. Strong lipid affinity of the ectodomain suggests that its heptad repeat regions play an active role in destabilizing membranes by directly binding to the lipid bilayers and thereby lowering the free-energy barrier for membrane fusion. In such a model, immediately following the shedding of gp120, the N-heptad and C-heptad helices dissociate and melt into the host cell and viral membranes, respectively, pulling the destabilized membranes into juxtaposition, ready for fusion. Post-fusion, reaching the final 6-helix bundle (6HB) conformation then involves competition between intermolecular interactions needed for formation of the symmetric 6HB trimer and the membrane affinity of gp41's ectodomain, including its membrane-proximal regions. Our solution NMR study of the structural and dynamic properties of three constructs containing the ectodomain of gp41 with and without its membrane-proximal regions suggests that these segments do not form inter-helical interactions until the very late steps of the fusion process. Interactions between the polar termini of the heptad regions, which are not associating with the lipid surface, therefore may constitute the main driving force initiating formation of the final post-fusion states. The absence of significant intermolecular ectodomain interactions in the presence of dodecyl phosphocholine and bicelles consisting of DMPC and dihexanoyl phosphatidylcholine suggested the importance of trimerization of gp41s transmembrane helix to prevent complete dissociation of the trimer during the course of fusion. The membrane proximal external region (MPER) of HIV-1 gp41 contains epitopes for at least four broadly neutralizing antibodies. Depending on solution conditions and construct design, different structures have been reported for this segment. We have found that in aqueous solution the MPER fragment (gp160 residues 660-674) exists in a monomer-trimer equilibrium with an association constant in the micro-molar range. Thermodynamic analysis revealed that the association is exothermic, more favorable in D2O than H2O, and increased with ionic strength, indicating hydrophobically driven intermolecular interactions. Circular dichroism, 13C chemical shifts, NOE, and hydrogen exchange rates revealed that MPER undergoes a structural transition from predominately unfolded monomer at low concentrations to an alpha-helical trimer at high concentrations. This result has implications for antibody recognition of MPER prior to and during the process where gp41 switches from a pre-hairpin intermediate to its post-fusion 6-helical bundle state. Preliminary experiments applied to the ecto-domain of the Spike protein of SARS-CoV-2 indicate this protein contains a three-helical N-terminal heptad repeat (NHR) that is considerably more stable than the corresponding region of gp41, and the propensity for the C-terminal heptad (CHR) repeat albeit lower than that of NHR, is also substantially higher than for the CHR of gp41, whereas the propensity to trimerize for its membrane proximal region is substantially lower. Work has been submitted for publication but remains under review.", "keywords": [ "2019-nCoV", "Affinity", "Antibodies", "Binding", "C-terminal", "Capsid Proteins", "Cell membrane", "Cells", "Chemicals", "Circular Dichroism", "Detergents", "Dissociation", "Ebola", "Epitopes", "Equilibrium", "Free Energy", "Glycoproteins", "HIV Envelope Protein gp120", "HIV-1", "Hemagglutinin", "Hydrogen", "Hydrophobicity", "Influenza", "Ionic Strengths", "Lecithin", "Lipid Bilayers", "Lipids", "Mediating", "Membrane", "Membrane Fusion", "Micelles", "Modeling", "Molecular Conformation", "N-terminal", "Phosphorylcholine", "Play", "Process", "Property", "Proteins", "Publications", "Reporting", "Role", "Structure", "Surface", "Tertiary Protein Structure", "Thermodynamics", "Transmembrane Domain", "Viral", "Viral Fusion Proteins", "Virus", "Work", "aqueous", "biophysical techniques", "design and construction", "driving force", "experimental study", "gp160", "influenzavirus", "intermolecular interaction", "melting", "monomer", "neutralizing antibody", "prevent" ], "approved": true } }, { "type": "Grant", "id": "7730", "attributes": { "award_id": "1ZIAAI001281-01", "title": "Effect of SARS-CoV-2 on host metabolism and its influence on innate and adaptive immunity", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 71008, "principal_investigator": { "id": 23525, "first_name": "Catharine", "last_name": "Bosio", "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": "Pulmonary infections represent 5 of the 30 most common causes of death around the world, with lower respiratory infections resulting on average of 4 million deaths each year and the leading cause of death among children under the age of 5. We are currently in the midst of a pandemic caused by the pulmonary pathogen SARS-CoV-2. To date, the number of infections and deaths have surpassed other more typical respiratory infections with over 21.5 million cases and 770,000 deaths. Since this is a new virus, there is very little we understand about all facets of the disease (COVID-19) it causes. The IPP section has over a decade of experience dissecting the innate and adaptive immune responses to pulmonary pathogens. Thus, in this project we leverage that experience to define unique features of both innate and adaptive immune responses to this virus with a special emphasis on the metabolic and lipidomic perturbations occurring during sub-lethal and lethal disease. Specific Aim 1: Identify the lipid signatures associated with mild, moderate and severe disease in humans. Lipids and lipid mediators are important molecules for initiating and maintaining inflammatory responses as well as resolving inflammation post-infection. Fortunately, many of these mediators are either targetable with established therapeutics and dosable with drugs that are undergoing early clinical trials. Thus, identification of lipid mediators that are correlated with progression or resolution of SARS-CoV-2 infection provides new therapeutic targets. Working with collaborators at Yale University, we obtained over 50 serum samples from healthy controls (collected prior to the pandemic), individuals with moderate disease, and individuals with sever disease. We identified a distinct signature of lipid mediators that were from the eicosanoid family that was correlated with sever disease. We will continue to utilize this approach to test serum from new collaborators from both within and outside NIH with the goal of identifying new therapeutic targets of eicosanoids that are detrimental or aid in resolution of SAR-CoV-2 infection. Specific Aim 2: Characterize the metabolic shifts in the host that are associated with sub-lethal and lethal SARS-CoV-2 infections in mice Specific shifts in metabolism are critical for mounting effective innate and adaptive immune responses. Using other models of infection we have found that pathogens can influence the ability of the host to properly regulate these shifts. Further, different tissues have differing abilities to mobilize metabolic pathways which also impacts disease progression and resolution. Using a variety of in vivo and in vitro techniques including but not limited to live animal imaging, assessment of metabolites and lipids from target and peripheral tissues, flow cytometry and assessment of metabolic flux in vitro we will determine how SARS-CoV-2 infection alters host metabolism to cause disease. Additionally, we will determine which pathways and mediators are required to resolve infection. By overlaying these results with those we obtain from human samples we will identify new targets for therapeutic intervention for SARS-CoV-2. Specific Aim 3: Identify the role of resident versus circulating T cells in protection against SARS-CoV-2 infection in mice. Generation and retention of T cells in the lung following sub-lethal infection or vaccination is essential for development of effective, long lasting immunity. Currently, there is no data concerning the presence or absence of resident T cells directed against SARS-CoV-2 among hosts that have either resolved infection or received a vaccine. We will determine if hosts that survive a sublethal infection develop a population of resident T cells in the lung. We will also characterize the phenotype and function of these cells and determine if they play a role in mediating protection against secondary infection.", "keywords": [ "2019-nCoV", "Age", "Animals", "COVID-19", "Cause of Death", "Cell physiology", "Cells", "Cessation of life", "Child", "Data", "Development", "Disease", "Disease Progression", "Dose", "Eicosanoids", "Elements", "Family", "Flow Cytometry", "Generations", "Genomics", "Goals", "Human", "Imaging technology", "Immune", "Immunity", "In Vitro", "Individual", "Infection", "Inflammation", "Inflammatory Response", "Lipids", "Location", "Lower Respiratory Tract Infection", "Lung", "Lung infections", "Mediating", "Mediator of activation protein", "Metabolic", "Metabolic Pathway", "Metabolism", "Modeling", "Mus", "Natural Immunity", "Organ", "Pathogenesis", "Pathway interactions", "Peripheral", "Pharmaceutical Preparations", "Phenotype", "Play", "Population", "Primary Infection", "Resolution", "Respiratory Tract Infections", "Role", "Sampling", "Serum", "T-Lymphocyte", "Techniques", "Testing", "Therapeutic", "Therapeutic Intervention", "Tissues", "United States National Institutes of Health", "Universities", "Vaccination", "Vaccines", "Virus", "adaptive immune response", "adaptive immunity", "animal imaging", "cell type", "early phase clinical trial", "experience", "in vivo", "lipid mediator", "metabolomics", "mouse model", "multiple omics", "new therapeutic target", "novel therapeutics", "novel vaccines", "pandemic disease", "pathogen", "prevent", "secondary infection" ], "approved": true } }, { "type": "Grant", "id": "7738", "attributes": { "award_id": "1ZIAHL001050-23", "title": "Molecular Dynamics Simulations Of Biological Macromolecules", "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": 1067238, "principal_investigator": { "id": 23533, "first_name": "Bernard R", "last_name": "Brooks", "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": "pH dependance of a Na channel Sodium ion channels play an important role in electrical signaling in cells; as such they are the targets of many drugs, as well as naturally occurring toxins from plant and animal sources. Inhibition and/or improper functioning of sodium channels due to mutation can lead to disease. In bacterial voltage gated sodium channels, the passage of sodium ions through the pore is controlled by a selectivity filter (SF) comprised of four glutamate residues. The number of ions bound in the channel can vary, but is about 2 on average. We have shown with MD simulations at constant pH and with free energy perturbation that the pKa values of the four SF glutamate residues depend on the number of ions bound in the channel. With 2 or 3 ions bound, at physiological pH, the SF is most likely in fully deprotonated state, and possibly also the singly protonated state. With 1 or 0 ions bound, the doubly protonated state can also get populated. Based on the MD simulations of the fully open channel, we have further shown that the conductance of the channel decreases with each proton bound to the SF. Thus the conductance of the channel is pH dependent, and decreases with lowering of pH. We also show that the conductance depends on the lipid composition of the membrane. The mechanisms involved in modulation of the channel conductances involves changes in the radius of the gate and the SF, as well as the electric field in the pore. Mechanism of degradation of Histatin 5 peptide by Secreted Aspartic Protease (SAPS) of C. Albicans This project started with testing the double link atom (DLM) methodology to treat the boundary between QM and MM regions on Amino Acids. The charge of MM link atom for Amino Acids was optimized by minimizing the difference between the dipole of the molecule before and after removing the QM part. Next, mechanism of cleavage of Hst5 by Sap-2 the major produced Aspartic Protease of C. Albicans and the effect of mutation on the cleavage process was studied with QM/MM methodology. Docking the peptide to the active site of Saps is performed by restraining the distance between the active site aspartic (Asp) residues and the lysine (Lys) residue on Hst5. To find difference between binding of Hst5 and its mutants to SAP we performed replica exchange umbrella sampling (REUS) of the peptide by pulling the peptide from active site to bulk water phase. The results showed a -11 kcal/mol free energy of binding for Hst5 to SAP. Initial conformation for quantum region is obtained by putting a harmonic restraint between Lys of the peptide and Asp of the enzyme and it is observed that water molecules occupy the active site. Intermediate and product states of the reaction are produced by restrained QMMM optimization with DFT level of theory for quantum region. The mechanism involves a tetrahedral gem-diol intermediate state which then leads to amide bond hydrolysis. A replica path method in CHARMM was used to find transition state and minimum energy path (MEP) of the reaction with Hartree Fock (HF) level of theory of QM region with 6-31G basis set. It was found that the formation of the intermediate state is the limiting step of the reaction. However, a higher level of theory and a more complex basis set is now being used to confirm these results. In the next step, we will use the optimized reaction path to start an off-path sampling which allows us to find the free energy of the reaction. Critical Sequence Hot-spots for Binding of nCOV-2019 to ACE2 as Evaluated by MD simulations: The novel coronavirus (nCOV-2019) outbreak has put the world on edge, causing millions of cases and hundreds of thousands of deaths all around the world, as of June 2020, let alone the societal and economic impacts of the crisis. The spike protein of nCOV-2019 resides on the virions surface mediating coronavirus entry into host cells by binding its receptor binding domain (RBD) to the host cell surface receptor protein, angiotensin converter enzyme (ACE2). In this study we have provided a detailed structural mechanism of how nCOV-2019 recognizes and establishes contacts with ACE2 and its difference with an earlier coronavirus SARS-COV in 2002 via extensive molecular dynamics (MD) simulations. Our results showed that nCOV-2019 RBD binds ACE2 with a significantly higher affinity () than SARS-COV which correlates with its higher infection rate. A per-residue free energy decomposition pinpointed the critical role of nCOV-2019 RBD residues Lys417, Tyr505, Gln498, Gln493 in binding ACE2. Numerous mutations have been identified in the RBD of nCOV-2019 strains isolated from humans in different parts of the world. In this study, we investigated the effect of these mutations as well as other Ala-scanning mutations on the stability of RBD/ACE2 complex. It is found that most of the naturally occurring mutations to the RBD either slightly strengthen or have the same binding affinity to ACE2 as the wild-type nCOV-2019. This means the virus had sufficient binding affinity to its receptor at the beginning of the crisis. This also have implications for any vaccine design endeavors since these mutations could act as antibody escape mutants. Furthermore, in-silico Ala-scanning and long-timescale MD simulations, highlight the crucial role of the residues at the interface of RBD and ACE2 that may be used as potential pharmacophores for any drug development endeavors. From an evolutional perspective, this study also identifies how the virus has evolved from its predecessor SARS-COV and how it could further evolve to become even more infectious. Exploring dynamics and network analysis of spike glycoprotein in SARS-COV-2 The ongoing pandemic caused by coronavirus SARS-COV-2 continues to rage with devastating consequences on human health and global economy. A spike glycoprotein on the surface of coronavirus mediates its entry into host cells and is the target of all antibody design efforts to neutralize the virus. The glycan shield of the spike helps the virus to evade the human immune response by providing a thick sugar-coated barrier against any antibody. To study the dynamic motion of glycans in the spike protein we performed microsecond-long MD simulation on the spike protein in two different states that correspond to the receptor binding domain in open or closed conformations. Analysis of this microsecond-long simulation revealed a scissoring motion on the N-terminal domain of neighboring monomers in the trimer. Role of multiple glycans in shielding of spike protein in different regions were uncovered by a network analysis. Centrality measurements in graph theory helped us identify glycans that play local or global roles in the network. It was found that the stalk region glycans have high local centralities which give rise to an effective shielding of this domain. On the other hand, breaches can be found in the apex of the spike protein for antibodies to bind and neutralize the virus. Role of several glycan such as N234 and N165 were pinpointed in the network of glycan. Microdomains of glycans were identified featuring a high degree of intra-communication in these microdomains and therefore most antibodies would bind to regions between these microdomains. An antibody overlap analysis revealed the glycans microdomains as well as individual glycans that inhibit access to the antibody epitopes on the spike protein. Our analysis showed that the spike protein is more vulnerable to antibodies when the RBD is in the open state. Overall, the results of this study provide detailed understanding of the spike glycan shield which must be considered for any rational antibody design project.", "keywords": [ "2019-nCoV", "Active Sites", "Address", "Affinity", "Amides", "Amino Acids", "Angiotensins", "Animal Sources", "Antibodies", "Aspartic Endopeptidases", "Basic Science", "Binding", "Biological", "Biophysics", "Candida albicans", "Cell Surface Receptors", "Cells", "Cessation of life", "Charge", "Communication", "Complex", "Computational Biology", "Coronavirus", "Development", "Disease", "Disease Outbreaks", "Docking", "Electron Microscopy", "Enzymes", "Epitopes", "Escape Mutant", "Evaluation", "Evolution", "Free Energy", "Gene Expression Profiling", "Glutamates", "Glycols", "Glycoproteins", "Health", "Hot Spot", "Human", "Hydrolysis", "Image Analysis", "Immune response", "Individual", "Ions", "Laboratories", "Lead", "Link", "Lipids", "Lysine", "Measurement", "Mediating", "Membrane", "Methodology", "Methods", "Modeling", "Molecular Conformation", "Motion", "Multienzyme Complexes", "Mutation", "N-terminal", "National Heart Lung and Blood Institute", "Pathway Analysis", "Peptides", "Pharmaceutical Preparations", "Phase", "Physiological", "Plant Sources", "Play", "Polysaccharides", "Process", "Proteins", "Protons", "Quantum Mechanics", "Quantum Theory", "Radial", "Reaction", "Research", "Research Project Grants", "Role", "SARS coronavirus", "Sampling", "Scanning", "Science", "Scientist", "Signal Transduction", "Sodium Channel", "Structure", "Structure-Activity Relationship", "Surface", "System", "Techniques", "Testing", "Thick", "Toxin", "Vaccine Design", "Virion", "Virus", "Water", "base", "biophysical properties", "design", "drug development", "economic impact", "electric field", "graph theory", "histatin 5", "in silico", "infection rate", "interest", "macromolecule", "molecular dynamics", "molecular mechanics", "molecular modeling", "monomer", "mutant", "mutation screening", "novel coronavirus", "pandemic disease", "pharmacophore", "programs", "quantum", "receptor", "receptor binding", "restraint", "simulation", "small molecule", "sodium ion", "sugar", "theories", "tool", "voltage" ], "approved": true } }, { "type": "Grant", "id": "7717", "attributes": { "award_id": "1ZIAAG000778-04", "title": "The role of immune cells in Alzheimer's disease", "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": [], "start_date": null, "end_date": null, "award_amount": 528921, "principal_investigator": { "id": 23510, "first_name": "Arya", "last_name": "Biragyn", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1613, "ror": "https://ror.org/049v75w11", "name": "National Institute on Aging", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1613, "ror": "https://ror.org/049v75w11", "name": "National Institute on Aging", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "The role of B cells in Alzheimer's disease (AD) remains poorly understood even though we and others showed their benefit as producers of antibody that help to eliminate neurotoxic beta-amyloid depositions (Ab plaques) (Olkhanud et al, Vaccine, 2011). About 6 years ago, we have hypothesized that B cells could also be promoting AD because they upregulate expression of inflammatory factors together with the onset of AD in 3xTgAD mice. We tested this possibility in 3 different mouse models of AD, such as 3xTgAD, APP/PS1 and 5xFAD mice, utilizing complementing experimental strategies. First, we generated B-cell deficient (BKO) mice that develop AD in young and old age, 2xTgAD and 3xTgAD mice by crossing BKO mice with 2xTgAD and 3xTgAD mice, respectively. The loss of B cells in these mice almost completely reversed the AD symptoms despite expression of AD-promoting transgenes. Compared to age/sex-matched B-cell sufficient littermates, 2xTgAD/BKO and 3xTgAD/BKO mice exhibited reduced anxiety and improved memory deficits. Both 2xTgAD/BKO and 3xTgAD/BKO mice contained significantly fewer Ab-plaques in the brain subiculum than their age- and sex-matched littermates. The over activated microglia, another hallmark of AD pathology, in both mice without B cells was also markedly reduced. To confirm this finding, we also transiently depleted B cells from the circulation of mice with AD, such as 3xTgAD, APP/PS1 and 5xFAD mice, by injecting CD20-targeting antibody. The B-cell depletion indeed significantly delayed AD symptoms in all three types of mice. Overall, for the first time we demonstrate that B cells play pathogenic role in AD and, importantly, their transient depletion from the circulation can delay AD onset. The paper, which we recently submitted for publication, came back for revision. Due to the COVID-19 quarantine, we had to terminate experiments and cull essential AD mice, precluding a proper addressing the editor and reviewers comments. We therefore expect to finalize this paper by middle of 2021. Despite this, we have played the key roles in successful completion of 2 papers from our collaborators on Ad and AD-like symptoms in Down syndrome.", "keywords": [ "APP-PS1", "Address", "Age", "Aging", "Alzheimer&apos", "s Disease", "Alzheimer&apos", "s disease model", "Alzheimer&apos", "s disease pathology", "Antibodies", "Anxiety", "B-Lymphocytes", "Back", "Blood Circulation", "Brain", "COVID-19", "Cells", "Complement", "Disease", "Down Syndrome", "Exhibits", "Goals", "Immune", "Inflammatory", "MS4A1 gene", "Memory impairment", "Microglia", "Mus", "Onset of illness", "Paper", "Pathogenicity", "Play", "Publications", "Published Comment", "Quarantine", "Role", "Symptoms", "Testing", "Therapeutic", "Time", "Transgenes", "Vaccines", "abeta deposition", "experimental study", "improved", "mouse model", "neurotoxic", "sex" ], "approved": true } }, { "type": "Grant", "id": "7698", "attributes": { "award_id": "1ZICAI001226-03", "title": "Center for Human Immunology", "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": 3460631, "principal_investigator": { "id": 23492, "first_name": "Yasmine", "last_name": "Belkaid", "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": "In response to the SARS-CoV-2 pandemic we have made the technologies and platforms at CHI available for characterization of COVID-19 patient samples, as a priority ahead of our ongoing collaborative studies. By early April we had completed adaptation of our transcriptomic and flow cytometry platforms, and operating procedures, to begin analysing peripheral blood from Covid-19 patients. CHI began receiving samples from Northern Italy and CITE-Seq was performed for more than 100 samples in close collaboration with the Tsang lab. BCR sequencing and scATAC seq was performed for a subset of these, and proteomic analysis was obtained for all of the samples by outsourcing this work at SomaLogic. 27-color flow cytometry phenotyping was also performed by CHI to validate the novel CITE-seq platform. Further, CHIs automated pipeline was used to isolate high quality RNA from PAXgene samples of 200 Covid-19 samples, to be used for both RNA-Seq at CHI as well as distribution to the Goldbach-Mansky lab. Together these efforts have contributed to initial immune characterization of acutely infected Covid-19 patients. We hope these platforms can now be applied to new cohorts becoming available which are able to address questions such as variation in the outcomes of infection. In addition to this COVID work CHI has continued to advance its previous studies that comprise 25 active collaborations across 8 Institutes and the Clinical Center. These are divided into 3 stages: initiation/sample collection (12 studies), assay (8 studies), and analysis/write up (5 studies). These all comprise multi-modal high-dimensional immune phenotyping of primary human samples. The current studies include characterizing immune changes in vaccine trials (malaria, HSV), clinical intervention trials (lupus, CHAPLE), and cohort studies of rare diseases (mitochondrial dysfunction). One of the new studies added is an exciting collaboration with Kevin Hall at NIDDK to characterize immune differences after periods of highly controlled diet changes. The monoclonal antibody therapy study of CHAPLE disease patients, with Mike Lenardo, is an example of how high dimensional phenotyping can lead to better understanding of patient pathology, and may inform use of a nascent therapy. The proteomic changes we observed give basic biology insight into, in this case, CD55 function and the mechanisms of complement inhibition, and this work is under review at Nature Immunology. Studies published this year included an integrated proteomic and cellular phenotyping analysis of maternal peripheral blood in longitudinally sampled human pregnancies, and characterization of changes in peripheral blood during treatment of healthy subjects with statins, and obese individuals undergoing a clinical trial of colchicine treatment. To support CHIs mission we continue to develop wet-lab and computational infrastructure. For single cell sequencing technologies using the 10x platform, we have expanded the number of protein antigens measured in CITE-Seq, and developed scATAC-seq approaches with greater throughput and lower cost. CITE-Seq, in particular, led to a high-profile finding characterizing variation in baseline immune states that predicts immune responses (see section Scientific Advances). For flow cytometry, on a new Cytek Aurora we have validated a 27 color cytometry for broad immune phenotyping, as well as a 33 color T cell focused panel run after PMA stimulation to detect cells primed for production of characteristic cytokines or transcription factors. For flow cytometry analysis we are applying methods to enable conventionally gated populations to be recognized and interrogated using high dimensional parameters, to help overcome the difficulties of interpreting unbiased clustering of high dimensional data. For mass cytometry analysis we are finalising a package that uses high dimensional observations to discriminate only the subset of cells that respond in ex vivo stimulation assays, such as our mass cytometry assay that quantifies phosphorylation of 10 intracellular proteins, in addition to 20 cell phenotype markers, in response to 12 in vitro stimulation conditions. CHI also provides fee-for-service access to assays not otherwise accessible to NIH researchers. The SomaLogic proteomic assay has been run for over 1000 samples, for 8 investigators, in the last year. This included human and murine samples from serum, plasma, cerebrospinal fluid, bronchioalveolar lavage fluid, and tissue homogenates. We continue to monitor alternative platforms and have run tests on O-Link that is offering increasingly high parameter antibody based analysis, although currently plan to transition our SomaLogic platform from the current 1.3k antigen panel to an analysis of 4.5k antigens.", "keywords": [ "2019-nCoV", "Acute", "Address", "Antibodies", "Antigens", "Behavior", "Biological", "Biological Assay", "Biology", "Bronchoalveolar Lavage", "COVID-19", "Cells", "Cerebrospinal Fluid", "Characteristics", "Clinical", "Clinical Trials", "Cohort Studies", "Colchicine", "Collaborations", "Color", "Complement", "Computer Analysis", "Computer Models", "Coupled", "Cytometry", "Data", "Development", "Diet", "Disease", "Fee-for-Service Plans", "Flow Cytometry", "Goals", "Health", "Health Services Accessibility", "Human", "Immune", "Immune response", "Immunity", "Immunologic Monitoring", "Immunology", "Immunotherapy", "In Vitro", "Individual", "Infection", "Institutes", "Intervention", "Intervention Trial", "Italy", "Laboratories", "Lead", "Leadership", "Link", "Liquid substance", "Lupus", "Malaria", "Measures", "Methods", "Mission", "Modeling", "Monitor", "Monoclonal Antibody Therapy", "Mus", "National Institute of Allergy and Infectious Disease", "National Institute of Diabetes and Digestive and Kidney Diseases", "Nature", "Obesity", "Outcome", "Outsourcing", "Pathology", "Patients", "Phenotype", "Phosphorylation", "Plasma", "Population", "Pregnancy", "Procedures", "Production", "Proteins", "Proteomics", "Publishing", "RNA", "Rare Diseases", "Research Personnel", "Resources", "Review Committee", "Running", "Sampling", "Scientific Advances and Accomplishments", "Serum", "Services", "Simplexvirus", "System", "T-Lymphocyte", "Technology", "Testing", "Tissues", "Training", "United States National Institutes of Health", "Vaccination", "Variant", "Work", "Writing", "base", "clinical application", "clinical center", "cohort", "collaborative approach", "computer infrastructure", "coronavirus disease", "cost", "cytokine", "data mining", "data modeling", "design", "high dimensionality", "insight", "microbiome", "microbiome research", "microbiota", "mitochondrial dysfunction", "multidimensional data", "multimodality", "novel", "pandemic disease", "peripheral blood", "phenotypic biomarker", "programs", "recruit", "response", "sample collection", "single cell sequencing", "tool", "transcription factor", "transcriptome sequencing", "transcriptomics", "vaccine trial" ], "approved": true } }, { "type": "Grant", "id": "7722", "attributes": { "award_id": "1ZIAAI001297-01", "title": "Molecular pathogenesis of human coronaviruses", "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": 9073, "principal_investigator": { "id": 23513, "first_name": "Marshall", "last_name": "Bloom", "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": "Since early 2020, the COVID-19 pandemic, caused the novel -coronavirus SARS-CoV-2, has ravaged the world and has disrupted much biomedical research. Consequently, we decided to focus a portion of our efforts on human coronaviruses, like SARS-CoV-2 and the Middle East Respiratory Syndrome coronavirus or MERS-CoV. Both MERS-CoV and SARS-CoV-2 are high consequence viral pathogens with the capacity to cause severe human disease, and SARS-CoV-2 has established a raging pandemic. This very new project will apply pre-existing expertise against this new pathogen. Suppression of SARS-CoV-2 and MERS-CoV replication by FDA-approved drugs The recent emergence of SARS-CoV-2 in 2019 and the emergence of MERS-CoV and SARS-CoV-1 in the past 20 years highlight the necessity of broad-spectrum antivirals that suppress coronaviruses and can be deployed against currently circulating coronaviruses and coronaviruses that emerge in the future. Dr. Stacey Scroggs arrived in BVBVS 4 months before the COVID-19 shutdown truncated research. Briefly, based on her thesis work, we selected several fluoroquinolone antibiotics and evaluated their ability to suppress several SARS-CoV-2 and MERS-CoV. We evaluated the potency of enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin to suppress SARS-CoV-2 and MERS-CoV replication based Dr. Scroggss work cited in the previous section as well as the work of other suggesting anti-SARS activity of these compounds We demonstrated that at micromolar concentrations over 150 all four drugs suppress SARS-CoV-2 replication in Vero cells. The effective concentration 50 values (EC50) of these drugs against SARS-CoV-2 were between153.2M and 531.0M indicating that these 4 fluoroquinolones have low potency against SARS-CoV-2 and are unlikely to elicit a clinical benefit alone. The results for MERS-CoV were similar. Antiviral potency at these concentrations is not due to cellular toxicity as the Cytotoxic Concentration50 for all 4 drugs in both cell types are over 600M. Thus, it appears that the fluoroquinolones tested will not be useful therapeutics for these 2 high consequence coronaviruses. Although this is negative data, we feel it is noteworthy and it is being prepared for publication. Cellular mechanisms modulating replication of high consequence human coronaviruses. As noted in my other annual report, in the past year Dr. Dylan Flather continued to employ genome wide loss of function studies to identify cellular genes that modulate flavivirus infections. He will use his expertise in that area to examine 2 high consequence human coronaviruses, SARS-CoV-2 and MERS-CoV, as well as the common cold coronavirus HCoV-229e. Briefly, haploid mutagenized or Genome-Scale CRISPR Knock-Out (GecKO) lentiviral transduced cell pools, are being infected with MERS and our colleagues at CZ Biohub are doing the same with SARS-CoV-2 and HCoV-229E. Deep sequencing of surviving cell populations should allow for the identification of deleted genes that are putative pro-viral host factors, as cells lacking these genes persist in cell culture following infection. Genes identified in this manner will be grouped into functional groups. We have just initiated the MERS genome-wide screen and validation of protein hits will ensue. The pronounced ability of MERS-CoV to induce syncytia formation is a complicating factor that is being address by manipulating viral MOI and plating density of the cell libraries. SARS-CoV-2 and Animal Cell Lines. Building off of previous work with vector borne flaviviruses, we tested various animal cell lines for permissiveness to SARS-CoV-2 infection. The lines tested were mink lung, ferret brain, raccoon uterine, fox lung, opossum kidney, white tail deer brain, canine kidney, and woodchuck hepatocytes. While infectious virus was seen at 24 hours post infection (hpi), titers dropped throughout the remainder of the timepoints tested. Due to the lack of increasing replication throughout the growth curve, we cannot rule out residual inoculum accounting for the virus seen at 24hpi. We have decided not to further pursue this project. Anti-CD47 and anti-IL6 as SARS-CoV-2 Therapeutics. In collaboration with Dr. Kim Hasenkrugs group, we will be examining the use of anti-CD47 and anti-IL6 antibodies during SARS-CoV-2 infection. We hope to be able to use these antibodies as therapeutics to stop or, potentially, reverse the lung damage caused by SARS-CoV-2 infection. Dr. Hasenkrugs lab has previously show anti-CD47 can decrease antiviral immune responses, helping to limit inflammation and increase the rate of infection clearance.", "keywords": [ "2019-nCoV", "Accounting", "Address", "Animals", "Annual Reports", "Anti-CD47", "Antibiotics", "Antibodies", "Antiviral Agents", "Area", "Basic Science", "Biology", "Biomedical Research", "Brain", "COVID-19", "COVID-19 pandemic", "Canis familiaris", "Cell Culture Techniques", "Cell Density", "Cell Line", "Cells", "Ciprofloxacin", "Clinical", "Clustered Regularly Interspaced Short Palindromic Repeats", "Collaborations", "Common Cold", "Coronavirus", "Data", "Deer", "Didelphidae", "Drops", "FDA approved", "Ferrets", "Flavivirus", "Flavivirus Infections", "Fluoroquinolones", "Foxes", "Future", "Genes", "Genomics", "Giant Cells", "Growth", "Haploidy", "Hepatocyte", "Hour", "IL6 gene", "Image", "Immune response", "Infection", "Inflammation", "Integration Host Factors", "Interleukin-6", "Kidney", "Knock-out", "Levaquin", "Libraries", "Lung", "Middle East Respiratory Syndrome", "Middle East Respiratory Syndrome Coronavirus", "Mink", "Molecular", "Molecular Biology", "Moxifloxacin", "Pathogenesis", "Pharmaceutical Preparations", "Population", "Proteins", "Publications", "Raccoons", "Research", "Residual state", "SARS coronavirus", "Severe Acute Respiratory Syndrome", "Tail", "Testing", "Therapeutic", "Toxic effect", "Uterus", "Validation", "Vero Cells", "Viral", "Virus", "Woodchuck", "Work", "base", "cell type", "cellular transduction", "cytotoxic", "deep sequencing", "functional group", "genome wide screen", "genome-wide", "human coronavirus", "human disease", "infection rate", "lentivirally transduced", "loss of function", "lung injury", "novel", "novel coronavirus", "pandemic disease", "pathogen", "pathogenic virus", "permissiveness", "vector-borne", "virology" ], "approved": true } }, { "type": "Grant", "id": "7682", "attributes": { "award_id": "1ZIEBC011384-10", "title": "Anatomic Pathology Residency Program", "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": 852774, "principal_investigator": { "id": 23485, "first_name": "Frederic", "last_name": "Barr", "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": "Residents in the Anatomic Pathology Residency Program contribute to the clinical research program of the NCI and the NIH. Through their efforts as anatomic pathology residents in training, they help illuminate the pathological changes associated initial presentation and therapy of both neoplastic and non-neoplastic diseases and explore new techniques to improve diagnosis of these diseases. These residents are critical to the patient care activities of the NCI and the NIH, and contribute to the diagnosis and management of disease, especially COVID-19 this year. Residents have also contributed to publications dealing with characterization, diagnosis, and pathogenesis of a number of disease entities.", "keywords": [ "Accreditation", "Anatomy", "Area", "Autopsy", "Biological Assay", "COVID-19", "Case Study", "Clinical", "Clinical Research", "Clinical Trials", "Clonality", "Communicable Diseases", "Consult", "Consultations", "Cytopathology", "DNA Methylation", "DNA analysis", "Diagnosis", "Diagnostic", "Digestive System Disorders", "Disease", "Disease Management", "Educational process of instructing", "Enrollment", "Etiology", "Exposure to", "Extramural Activities", "Flow Cytometry", "Fluorescent in Situ Hybridization", "Functional disorder", "Funding", "Gene Mutation", "Genes", "Genetic study", "Hematopathology", "Institutes", "Investigation", "Kidney Diseases", "Laboratories", "Learning", "Lymphoid", "Malignant Neoplasms", "Medicine", "Mission", "Molecular Genetics", "Mutation", "Oncology", "Outcome", "Pathogenesis", "Pathologic", "Pathology", "Patient Care", "Patients", "Philosophy", "Play", "Protocols documentation", "Publications", "Research", "Research Activity", "Research Training", "Residencies", "Role", "Services", "Surgical Pathology", "Techniques", "Tissues", "Training", "Training Programs", "United States National Institutes of Health", "base", "cancer therapy", "clinical center", "disease diagnosis", "epidemiology study", "experience", "improved", "insight", "molecular diagnostics", "neoplastic", "nervous system disorder", "neuropathology", "next generation sequencing", "novel", "programs", "recruit", "research clinical testing", "soft tissue", "urologic" ], "approved": true } }, { "type": "Grant", "id": "7740", "attributes": { "award_id": "1ZIAMH002969-02", "title": "Unit on Neuroscience and Novel Therapeutics", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Mental Health (NIMH)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 1425268, "principal_investigator": { "id": 23535, "first_name": "Melissa", "last_name": "Brotman", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1604, "ror": "https://ror.org/04xeg9z08", "name": "National Institute of Mental Health", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1604, "ror": "https://ror.org/04xeg9z08", "name": "National Institute of Mental Health", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "In 2020, our program completed a randomized controlled trial (N=44, active vs. placebo) of a computer-based treatment engaging behavioral and neural targets of aberrant threat processing. In addition, we developed an analogous fMRI paradigm to probe neural correlates in a large (N>100) sample of youth with varying degrees of irritability. We found unique neural correlates associated with latent factor-derived phenotype of high irritability and anxiety. Second, we developed a novel frustration-exposure intervention for youth with severe irritability based on extinction principles. N=30 youth have been randomized; preliminary analyses demonstrated that irritability scores decreased significantly from the start of therapy to end of therapy. NNT acquires pre-treatment behavioral and task-based fMRI data to test the hypothesis that pre-treatment behavioral deficits in inhibition predict poorer treatment response. Third, we leverage technology to assess symptoms by utilizing digitally based event sampling (ecological momentary assessment). We have also developed a cognitive inhibition mobile application to probe children's inhibitory control. These interventions provide the foundation for scalable, target-based interventions which are more easily disseminated, facilitating public health impact. Fourth, as threats engage evolutionarily conserved processes, our translational perspective has been supported by two Bench-to-Bedside Awards. Specifically, we reverse translated the Human Intruder Paradigm, (Kalin & Shelton 1989) into two clinical paradigms. Our fMRI (N=60) and eye-tracking (N=60) tasks parallel work in non-human primates. Ultimately, these mechanistic studies will allow for more targeted interventions for pathological irritability. Finally, the acute onset of the COVID-19 pandemic provides a rare opportunity to utilize existing pre-stress clinical and neural data to predict stress-related increases in psychopathology and associated neural dysfunction. In this study, we are examining associations among stress, genetic liability, brain function, and the development of psychopathology.", "keywords": [ "Acute", "Address", "Affect", "Anxiety", "Award", "Base of the Brain", "Behavior Therapy", "Behavioral", "Behavioral Mechanisms", "Brain", "COVID-19 pandemic", "Child", "Childhood", "Clinical", "Clinical Trials", "Cognitive", "Complex", "Computer Models", "Computers", "Coupled", "Data", "Development", "Ecological momentary assessment", "Event", "Extinction (Psychology)", "Foundations", "Frustration", "Functional Magnetic Resonance Imaging", "Genetic", "Goals", "Human", "Impairment", "Intervention", "Lead", "Learning", "Mental disorders", "Metabolic", "Neuronal Dysfunction", "Neurosciences", "Outcome", "Pathologic", "Pharmaceutical Preparations", "Phenotype", "Placebos", "Process", "Protocols documentation", "Psychopathology", "Public Health", "Randomized", "Randomized Controlled Trials", "Sampling", "Social Environment", "Stress", "Symptoms", "Taxonomy", "Technology", "Testing", "Translating", "Work", "Youth", "base", "bench to bedside", "clinical phenotype", "digital", "mobile application", "mobile computing", "negative affect", "neural correlate", "neuromechanism", "nonhuman primate", "novel", "novel therapeutics", "programs", "psychologic", "relating to nervous system", "response", "side effect", "translational neuroscience", "treatment response", "visual tracking" ], "approved": true } }, { "type": "Grant", "id": "7736", "attributes": { "award_id": "1ZIAAI001280-01", "title": "Pathogenesis of SARSCov2 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": null, "end_date": null, "award_amount": 55722, "principal_investigator": { "id": 23532, "first_name": "Jason", "last_name": "Brenchley", "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": "Severe SARSCov2 disease occurs, predominantly, in humans with one of several preexisting conditions including cardiovascular disease, advanced age, obesity, and diabetes. These underlying conditions tend to have inflammation in common. Indeed, dexamethasone treatment is showing utility in COVID19. While the actual mechanisms underlying severe COVID19 are unclear increased coagulopathy seems to be common. Moreover, many individuals have evidence of GI tract involvement in their SARSCov2 infection with diarrhea and viral RNA being present in fecal samples. Individuals with high granulocyte to lymphocyte ratios also tend to be more common among groups with severe disease. We hypothesize the GI tract involvement of SARSCov2 infection leads to translocation of microbial products from the lumen of the GI tract into circulation and these lead to inflammation and coagulopathy. We aim to test the hypothesis that microbial translocation contributes to inflammation in SARSCov2 infection. We also aim to artificially elevate the granulocyte to lymphocyte ratio hypothesizing that this will exacerbate SARSCov2 disease. Finally, we aim to determine how, or if, preexisting immunity to common coronavirus (HKU1) influences subsequent SARSCov2 infection. These studies will involve longitudinal analysis of experimentally SARSCov2-infected Asian macaques. We will assess microbial translocation and the composition of the microbiome in animals and we will experimentally elevate the granulocyte to lymphocyte ratio with granulocyte stimulating factor prior to SARSCov2 infection. Finally, we will follow animals who had previously been experimentally infected with HKU1 and subsequently challenged with SARSCov2.", "keywords": [ "Animals", "Asians", "Benign", "Blood Circulation", "Blood Coagulation Disorders", "COVID-19", "Cardiovascular Diseases", "Cessation of life", "Coronavirus", "Dexamethasone", "Diabetes Mellitus", "Diarrhea", "Disease", "Disease Progression", "Elderly", "Gastrointestinal tract structure", "Goals", "Human", "Immunity", "Incidence", "Individual", "Infection", "Inflammation", "Lead", "Lymphocyte", "Macaca", "Obesity", "Pathogenesis", "Risk Factors", "Sampling", "Testing", "Work", "experimental analysis", "granulocyte", "longitudinal analysis", "microbial", "microbiome composition", "neutrophil", "nonhuman primate", "viral RNA" ], "approved": true } } ], "meta": { "pagination": { "page": 3, "pages": 1392, "count": 13920 } } }