Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1384&sort=award_id
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=award_id", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1442&sort=award_id", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1385&sort=award_id", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1383&sort=award_id" }, "data": [ { "type": "Grant", "id": "9222", "attributes": { "award_id": "5R35GM138029-02", "title": "Determining mechanisms of innate immune modulation by ADP-ribosylation", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 22244, "first_name": "MICHAEL", "last_name": "SAKALIAN", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-09-15", "end_date": "2025-08-31", "award_amount": 359604, "principal_investigator": { "id": 24962, "first_name": "Anthony R", "last_name": "Fehr", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1496, "ror": "", "name": "UNIVERSITY OF KANSAS LAWRENCE", "address": "", "city": "", "state": "KS", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1496, "ror": "", "name": "UNIVERSITY OF KANSAS LAWRENCE", "address": "", "city": "", "state": "KS", "zip": "", "country": "United States", "approved": true }, "abstract": "ADP-ribosylation is an important post-translational modification that directly influences several biological processes including cancer, allergy, and infectious disease. ADP-ribose can be added to proteins as one or more consecutive units by ADP-ribosyltransferases, also termed PARPs, resulting in mono- or poly- ADP-ribosylation (mAR or pAR). Most mARylating PARPs are upregulated by interferon (IFN) upon virus infection and several are predicted to have antiviral functions. In addition, several viral families, including the Coronaviridae and Togaviridae, encode for macrodomain proteins that have mono-ADP-ribosyl hydrolase (ARH) activity. This activity allows these viruses the ability to specifically counteract the effects of mAR, further implicating mAR in the mammalian antiviral response. Despite these findings, there are only a few known examples where mAR is known to inhibit virus replication. This is largely due to the lack of cell culture models of virus infections where the mAR status of a cell can be specifically controlled, such as models using mutant viruses or PARP knockout cells that have significant phenotypes. Importantly, the PI has established a virus infection system using a model coronavirus, Murine Hepatitis Virus (MHV), where virus lacking ARH activity is i) significantly impaired in virus replication and ii) independently induces a robust IFN response. These phenotypes are reversed by PARP inhibitors, establishing mAR as a key factor driving this anti-viral response. The investigator’s long-term goal is to determine mechanistically how mAR inhibits virus replication and enhances the innate immune response following virus infection. This gap in knowledge will be resolved by answering the following questions: 1) How does mAR inhibit MHV infection? Does it inhibit the entry, RNA replication, protein translation, assembly, or release of MHV? 2) What step(s) of the IFN induction pathway is enhanced by mAR, and does mAR also affect the IFN response in bats, which are known to harbor many highly pathogenic viruses? 3) What proteins are modified by PARPs following virus infection and which substrates are relevant for specific phenotypes? The rationale for this research is that it will enhance our understanding of mAR, including its ability to modulate protein function and will uncover novel cellular proteins or processes that mediate virus replication. The work is innovative because: i) it will bridge a significant knowledge gap between ADP-ribose biology, the innate immune response, and virus replication; ii) it utilizes unique models of infection utilizing both mutant viruses and PARP knockout cells; and iii) will be the first to address the role of mAR in bats. Finally, these projects are significant and relevant to the NIGMS mission because they will provide a thorough understanding of how mAR impacts the anti-viral response that could lay the foundation for advances in the treatment of virus infections or other human diseases impacted by mAR.", "keywords": [ "ADP Ribose Transferases", "ADP ribosylation", "Address", "Adenosine Diphosphate Ribose", "Affect", "Antiviral Agents", "Antiviral Response", "Antiviral Therapy", "Automobile Driving", "Biological Process", "Biology", "Cell Culture Techniques", "Cells", "Chiroptera", "Communicable Diseases", "Coronavirus", "Family", "Foundations", "Goals", "Hydrolase", "Hypersensitivity", "Immune response", "Impairment", "Infection", "Innate Immune Response", "Interferons", "Knock-out", "Knowledge", "Lead", "Malignant Neoplasms", "Mediating", "Mission", "Modeling", "Murine hepatitis virus", "National Institute of General Medical Sciences", "Pathway interactions", "Phenotype", "Phosphorylation", "Post-Translational Protein Processing", "Process", "Proteins", "RNA replication", "Research", "Research Personnel", "Role", "System", "Togaviridae", "Translations", "Viral", "Viral hepatitis", "Virus", "Virus Diseases", "Virus Replication", "Work", "human disease", "immunoregulation", "inhibitor/antagonist", "innate immune mechanisms", "innovation", "mutant", "novel", "pathogenic virus", "protein function", "response" ], "approved": true } }, { "type": "Grant", "id": "6735", "attributes": { "award_id": "5R35GM140822-02", "title": "Extracellular miRNAs, innate immunity, and critical illness", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 22508, "first_name": "CHIEN-CHUNG", "last_name": "Chao", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-05-01", "end_date": "2026-02-28", "award_amount": 347625, "principal_investigator": { "id": 22509, "first_name": "WEI", "last_name": "CHAO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 793, "ror": "", "name": "UNIVERSITY OF MARYLAND BALTIMORE", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 793, "ror": "", "name": "UNIVERSITY OF MARYLAND BALTIMORE", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "Sepsis and ischemic myocardial infarction (MI) are two critical illnesses with very high mortality. While their etiologies are distinctively different, they share similar features of innate immune activation, marked tissue inflammation, and acute cardiac dysfunction. Tissue inflammation, largely driven by innate immunity activation, is a major determinant of cardiac injury in sepsis and myocardial ischemia-reperfusion (I/R). We have found that host cellular RNA and various miRNAs are released into the blood during murine/human sepsis and myocardial I/R. Circulating host RNA is closely correlated with sepsis severity and contributes to myocardial I/R injury in animals. RNAseq reveals that miRNAs are the dominant biotype (70%) of plasma RNAs in both healthy and septic mice and human. Moreover, we have reported that these extracellular (ex)-RNAs and certain uridine-rich ex-miRNAs function as a damage-associated molecular pattern (DAMP) and drive innate immune response through a TLR7-dependent pathway. Using a computer algorithm, we have identified two miRNA sequence motifs proven to be essential for miRNA-induced innate immunity activation. Finally, genetic deletion of TLR7 attenuates cytokine storm/coagulopathy and improves survival in sepsis animals. The goal of this research program is to delineate the function and mechanism of ex-miRNAs in innate immunity activation and in the pathogenesis of sepsis and myocardial I/R injury. Specifically, we will address the following 3 key questions: 1) What are the roles of ex-miRNAs in systemic innate immunity activation and cardiac dysfunction in sepsis, and in myocardial inflammation and infarction following I/R? 2) What are the underlying mechanisms responsible for ex-miRNA-mediated cardiac injury and dysfunction during sepsis and myocardial I/R? 3) Can we develop an anti-miRNA or anti-TLR7 strategy to attenuate sepsis-induced cardiomyopathy and improve survival, and to reduce myocardial injury after I/R? We will use both mouse models and biospecimens/clinical data of septic patients. The proposed work represents a paradigm shift in miRNA biology – its unique function as a DAMP in innate immunity and in two critical illnesses that are dominated by innate immunity-driven inflammation.", "keywords": [ "Acute", "Address", "Animals", "Attenuated", "Biology", "Blood", "Blood Coagulation Disorders", "Cardiomyopathies", "Clinical Data", "Computational algorithm", "Critical Illness", "Disease", "Etiology", "Genetic", "Goals", "Grant", "Heart Injuries", "Human", "Infarction", "Inflammation", "Innate Immune Response", "Ischemia", "Mediating", "MicroRNAs", "Molecular", "Mus", "Myocardial", "Myocardial Infarction", "Myocardial Ischemia", "Myocardial dysfunction", "Natural Immunity", "Pathogenesis", "Pathway interactions", "Pattern", "Plasma", "RNA", "Reperfusion Injury", "Reperfusion Therapy", "Reporting", "Research", "Research Support", "Role", "Sepsis", "Severities", "TLR7 gene", "Tissues", "Uridine", "Work", "cytokine release syndrome", "extracellular", "immune activation", "improved", "mortality", "mouse model", "myocardial injury", "organ injury", "programs", "septic", "septic patients", "transcriptome sequencing" ], "approved": true } }, { "type": "Grant", "id": "6888", "attributes": { "award_id": "5R35GM140881-02", "title": "CD4 T cell dysfunction and reprogramming during sepsis", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 22300, "first_name": "XIAOLI", "last_name": "Zhao", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-05-01", "end_date": "2026-04-30", "award_amount": 387500, "principal_investigator": { "id": 22724, "first_name": "Thomas S", "last_name": "Griffith", "orcid": null, "emails": "[email protected]", "private_emails": null, "keywords": "[]", "approved": true, "websites": "[]", "desired_collaboration": "", "comments": "", "affiliations": [ { "id": 764, "ror": "https://ror.org/017zqws13", "name": "University of Minnesota", "address": "", "city": "", "state": "MN", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 764, "ror": "https://ror.org/017zqws13", "name": "University of Minnesota", "address": "", "city": "", "state": "MN", "zip": "", "country": "United States", "approved": true }, "abstract": "Sepsis remains a major cause of death worldwide (11 million sepsis-related deaths were reported in 2017), and that costs associated with treating septic patients place a large burden on the healthcare industry. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Early stages of sepsis are marked by hyperinflammation driven by proinflammatory cytokines (i.e., IL-1β, IL-6, IFNγ, and TNF). Patients who survive the acute phase of sepsis display long-term impairments in immune function. This state of chronic immunoparalysis renders sepsis survivors increasingly susceptible to secondary infections. Consequently, there is a desperate need to better understand the cellular and molecular basis of acute sepsis pathophysiology and subsequent immune reprogramming that defines the prolonged immune suppression. CD4 T cells, essential for coordinating the cellular and humoral immune response to a range of pathogens under normal circumstances, are severely depleted during the acute stage of sepsis. The overall number of CD4 T cells gradually recover over time, but their functional capacity remains blunted for many months. For the past 10 years, we have focused our research to pursue the long-term goal of understanding how sepsis impacts the CD4 T cell compartment because of the key role played by CD4 T cells in the overall fitness of the immune system. We will continue our investigation of the cellular and molecular reprogramming of CD4 T cells during sepsis in three interconnected areas of future research: 1) Define the mechanism(s) by which regulatory CD4 T (Treg) cells expand during sepsis; 2) Perform an integrated discovery approach using genomics, proteomics, and metabolomics to elucidate the molecular basis of sepsis pathophysiology and CD4 T cell immunoparalysis; and 3) Determine how intestinal microbiota dysfunction during sepsis affects the magnitude of the cytokine storm and promotes CD4 T cell immunoparalysis and increased incidence of late-onset mortality. We will interrogate samples obtained from multiple cohorts of sepsis patients, as well as from preclinical mouse models of sepsis at the level of Ag-specific CD4 T cell populations. Our preclinical studies will be further strengthened by using a novel mouse model that mimics a critical aspect of human biology – exposure to multiple ongoing and resolved infections trains the immune system for robust responses to new pathogens – and will serve as an important and novel ‘transitional translational’ preclinical bridge between humans and SPF laboratory mice to mechanistically study CD4 T cell dysfunction and reprogramming during sepsis. Addressing these key gaps in knowledge regarding the effect of sepsis on CD4 T cell biology will likely reveal new points of intervention that can be exploited in the future to restore CD4 T cell-mediated immunity, and overall immune fitness, following sepsis.", "keywords": [ "Activities of Daily Living", "Acute", "Address", "Adult", "Affect", "American", "Area", "Back", "CD4 Positive T Lymphocytes", "Cause of Death", "Cell Compartmentation", "Cells", "Cellular Immunity", "Cellular biology", "Cessation of life", "Childhood", "Chronic", "Exposure to", "Functional disorder", "Future", "Genomics", "Goals", "Healthcare Industry", "Human", "Human Biology", "Immune", "Immune response", "Immune system", "Immunosuppression", "Impairment", "Incidence", "Infection", "Interferon Type II", "Interleukin-1 beta", "Interleukin-6", "Intervention", "Investigation", "Knowledge", "Laboratory mice", "Life", "Modeling", "Molecular", "Mus", "Nosocomial Infections", "Organ", "Patients", "Phase", "Play", "Population", "Proteomics", "Regulatory T-Lymphocyte", "Reporting", "Research", "Sampling", "Secondary to", "Sepsis", "Survivors", "TNF gene", "Time", "Training", "cohort", "cost", "cytokine", "cytokine release syndrome", "emerging pathogen", "fitness", "gut microbiota", "immune function", "metabolomics", "mortality", "mouse model", "novel", "pathogen", "pre-clinical", "preclinical study", "response", "secondary infection", "septic patients" ], "approved": true } }, { "type": "Grant", "id": "6747", "attributes": { "award_id": "5R35GM140887-02", "title": "Structural and Functional Roles of the Membrane-Related Components of Single-Pass Membrane Proteins", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 22539, "first_name": "Zhongzhen", "last_name": "Nie", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-05-01", "end_date": "2026-02-28", "award_amount": 397764, "principal_investigator": { "id": 22540, "first_name": "JAMES Jeiwen", "last_name": "CHOU", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 855, "ror": "", "name": "HARVARD MEDICAL SCHOOL", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "My laboratory investigates the structural and functional roles of the transmembrane (TM) and membrane- proximal (MP) regions of immune receptors and viral fusion proteins. The single-pass transmembrane (TM) proteins account for the vast majority of signaling receptors on the cell surface, and due to the lack of structural information, the TM/MP regions are often the missing link in our understanding of how extracellular ligand binding is translated to the activation of intracellular signaling pathways. TM and MP regions of single-pass membrane proteins are extremely difficult to visualize. We have developed an effective NMR/biochemistry technology platform for visualizing these regions and found that they can have surprisingly important biological function other than membrane anchoring. We find that a few receptors in the tumor necrosis factor receptor superfamily (TNFRSF) exhibit a previously unknown phenomenon that their transmembrane domains (TMDs) alone can oligomerize in membrane and drive receptor clustering and activation. In another finding, the TM region of the HIV-1 envelope spike form defined trimeric structure that can strongly influence the antigenicity of the ectodomain of the spike currently being used for vaccine development. The above few examples already suggest the enormous potential of uncovering the membrane regions of type I/II membrane proteins in discovering new biological mechanisms, which is the motivation for the proposed research. In the next five years, we will continue to explore the structure and function of TM regions with three specific goals. (1) We will further examine the mechanism of TMD-mediated receptor clustering and activation for other members of the TNFRSF and test the generality of this new concept in receptor biology. (2) We will explore the function of TMD oligomerization in the signaling mechanism of the chain cytokine receptors, for which the membrane regions are completely unknown. (3) We will continue to examine the TM and MP regions of other viral fusion proteins such as that of SIV and coronavirus, for understanding how the membrane-interacting components of the fusion proteins stabilize the prefusion state of the envelope spikes and for revealing unique structural features that may be used for testing mechanistic hypotheses of viral membrane fusion.", "keywords": [ "Agonist", "Antigens", "Biochemistry", "Biological", "Biological Process", "Biology", "Cell surface", "Chimeric Proteins", "Coronavirus", "Cytokine Receptors", "Development", "Exhibits", "Family", "Goals", "HIV vaccine", "HIV-1", "Immunologic Receptors", "Immunotherapy", "Integral Membrane Protein", "Interleukin Receptor", "Laboratories", "Ligand Binding", "Link", "Mediating", "Membrane", "Membrane Fusion", "Membrane Proteins", "Motivation", "Receptor Signaling", "Research", "Role", "SIV", "Signal Pathway", "Signal Transduction", "Structure", "Technology", "Testing", "Translating", "Transmembrane Domain", "Tumor Necrosis Factor Receptor", "Viral", "Viral Fusion Proteins", "coronavirus vaccine", "design", "extracellular", "insight", "member", "receptor", "vaccine development" ], "approved": true } }, { "type": "Grant", "id": "6856", "attributes": { "award_id": "5R35GM141089-02", "title": "Therapeutic Monoclonal Antibodies Inhibiting Proteases of Biomedical Importance", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 22689, "first_name": "Oleg", "last_name": "Barski", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-07-01", "end_date": "2026-04-30", "award_amount": 390000, "principal_investigator": { "id": 22690, "first_name": "Xin", "last_name": "Ge", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 788, "ror": "", "name": "UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON", "address": "", "city": "", "state": "TX", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 788, "ror": "", "name": "UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON", "address": "", "city": "", "state": "TX", "zip": "", "country": "United States", "approved": true }, "abstract": "As important signaling molecules, proteases precisely control a wide variety of physiological processes both in health and in diseases, and thus represent one of the largest families of pharmaceutical targets. Despite decades of intensive efforts, conventional drug discovery strategies have only achieved a limited success by targeting a small fraction of all therapeutically relevant proteases. It is because small-molecule inhibitors are often lack of specificity and/or appropriate pharmacokinetic properties required for effective and safe protease-based therapy. In these aspects, monoclonal antibodies (mAbs) are emerging as attractive alternatives with significant advantages such as high selectivity, long serum half-life, potential to cross the blood-brain barrier, and as inducible prodrugs. Since the invention of hybridoma technology, tremendous progress has been made in mAb discovery and engineering. However, routine discovery of protease-inhibiting mAbs is still a considerable challenge in general, due to the incompatibility of human antibody paratope for enzyme inhibition, and lack of functional high-throughput screening methods. My laboratory has been committed to the development of streamlined methodologies that facilitate the generation of therapeutic mAbs as safe and effective protease inhibitors. Over the past five years, we have made significant progress, and established a series of novel technologies, including camelid-inspired convex paratope human antibody libraries, and inhibition-based rather than binding-based selection/screening methods. Combining these enabling approaches, we discovered, characterized, and optimized panels of potent and specific mAbs inhibiting numerous proteases of biomedical importance. Furthermore, our protease inhibitory mAbs have shown significant therapeutic efficacy in mouse models of cancers, neuropathic pains, obesity, and stroke. By overcoming longstanding challenges, these achievements have opened the exciting opportunity. In the next five years, we will extend our powerful technologies to many other well-documented proteases, of which therapeutic inhibitors are urgently needed. Furthermore, we will develop additional technologies to achieve unique and therapy-desirable features: (1) function-specific (substrate-dependent) inhibition, (2) broad-spectrum inhibition on a group of proteases, and (3) epitope-specific inhibition by rational design. Overall, it has been estimated that proteases account for 5-10% of all drug targets have been studied for pharmaceutical development. The completion of proposed research will unambiguously advance therapeutic mAb developments targeting biomedically important proteases, e.g. against the present danger, SARS-CoV-2, by inhibiting TMPRSS2 (type II transmembrane serine protease) as a broad neutralization approach without the unwanted antibody-dependent enhancement.", "keywords": [ "2019-nCoV", "Achievement", "Antibodies", "Antibody Binding Sites", "Antibody-Dependent Enhancement", "Binding", "Blood - brain barrier anatomy", "Cancer Model", "Development", "Disease", "Drug Kinetics", "Drug Targeting", "Engineering", "Enzyme Inhibition", "Epitopes", "Family", "Generations", "Half-Life", "Health", "Human", "Hybridomas", "Laboratories", "Lead", "Malignant Neoplasms", "Methodology", "Methods", "Monoclonal Antibodies", "Obesity", "Pathogenesis", "Pathology", "Peptide Hydrolases", "Pharmacologic Substance", "Physiological Processes", "Prodrugs", "Property", "Protease Inhibitor", "Public Health", "Research", "Series", "Serine Protease", "Serum", "Signaling Molecule", "Specificity", "Stroke", "TMPRSS2 gene", "Technology", "Therapeutic", "Therapeutic Intervention", "Therapeutic Monoclonal Antibodies", "Treatment Efficacy", "Virus Diseases", "antibody inhibitor", "antibody libraries", "base", "design", "drug discovery", "high throughput screening", "inhibiting antibody", "inhibitor therapy", "invention", "mouse model", "new technology", "painful neuropathy", "programs", "protease E", "screening", "small molecule inhibitor", "success", "therapeutic development" ], "approved": true } }, { "type": "Grant", "id": "8497", "attributes": { "award_id": "5R35GM141818-02", "title": "Hybrid Methods for Dynamic Structure Analysis of Proteins from Pathogenic Microorganisms", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 23658, "first_name": "FRANK PAUL", "last_name": "Shewmaker", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-07-01", "end_date": "2026-04-30", "award_amount": 658000, "principal_investigator": { "id": 24259, "first_name": "GAETANO T", "last_name": "MONTELIONE", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 148, "ror": "https://ror.org/01rtyzb94", "name": "Rensselaer Polytechnic Institute", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 148, "ror": "https://ror.org/01rtyzb94", "name": "Rensselaer Polytechnic Institute", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "This research program will investigate the general hypothesis that understanding the conformational diversity of proteins will provide new insights into their biology, and enable medical research. It is directed to two classes of systems: Integral Membrane Proteins (IMPs) and viral-host interactions. IMPs play critical roles as gate keepers, receptors, transporters, homeostasis regulators, and drug targets. These functions are mediated by the conformational plasticity of the IMP in the membrane environment. IMPs are challenging to prepare, and even more challenging to reconstitute in appropriate membrane mimicking environments. Cost-effective technologies for isotope-enrichment in condensed volumes, hybrid approaches combining NMR with evolutionary co-variation (ECs), novel methods of contact prediction, and innovative modeling methods from the protein structure prediction community, will be applied to structure-function studies of IMPs. These IMPs, chosen from important human pathogens, including E. coli, K. pneumoniae, and P. aeruginosa, are potential targets for antibiotic discovery. ECs will also be combined with NMR data to determine structures of multiple “native states” of proteins. The second component of our program is directed to viral – host biomolecular complexes, and antiviral drug discovery. We will utilize innovative paramagnetic NMR methods, together with small angle X-ray scattering (SAXS), electron-electron double resonance spectroscopy (DEER), and Förster resonance energy transfer (FRET), to rigorously define dynamic interdomain structural distributions conferred by the partially-ordered linkers of the murine Moloney Leukemia Virus (MLV) integrase (IN). These data will be interpreted in the context of maximum occupancy probabilities (MaxOcc), and used to probe the role(s) of this flexibility in the gene integration mechanisms of g-retroviruses. Interdomain linkers also function to provide flexibility needed for binding partner promiscuity. We will also determine how the interdomain linker sequences of influenza Non-Structural Protein 1 (NS1) confer appropriate plasticity to define its specificity and affinity for host proteins and RNAs. This structural and functional promiscuity underlies NS1’s mechanisms for suppressing the cellular innate immune response to influenza infection, and rigorous characterization of its dynamic structural basis will provide fundamental information for live-attenuated virus vaccine development. We will also apply our platform to investigate drugs that inhibit SARS-CoV2 virus by binding its main protease (Mpro). We have identified three drugs, already approved for use in humans, originally designed to inhibit the NSP3/4A protease of hepatitis C virus, that also inhibit SARS-CoV2 in viral replication assays at low micromolar concentrations. Our computational docking studies have also identified several other FDA- approved drugs that may inhibit Mpro. Enzyme kinetic, biophysical chemistry, and X-ray crystallography studies will be used to characterize complexes formed between these protease inhibitor drugs and Mpro, and to develop their potential as COVID-19 therapeutics, or as lead compounds for new therapeutic development.", "keywords": [ "Affinity", "Antibiotics", "Antiviral Agents", "Attenuated Live Virus Vaccine", "Binding", "Biological Assay", "Biology", "COVID-19 therapeutics", "Communities", "Complex", "Coronavirus", "Data", "Docking", "Drug Targeting", "Electrons", "Environment", "Enzyme Kinetics", "Escherichia coli", "FDA approved", "Fluorescence Resonance Energy Transfer", "Gammaretrovirus", "Genes", "Genome", "Hepatitis C virus", "Homeostasis", "Human", "Hybrids", "Influenza", "Innate Immune Response", "Integral Membrane Protein", "Integrase", "Isotopes", "Klebsiella pneumoniae", "Lead", "Mediating", "Medical Research", "Membrane", "Methods", "Modeling", "Molecular Conformation", "Moloney Leukemia Virus", "Nonstructural Protein", "Pathogenicity", "Peptide Hydrolases", "Pharmaceutical Preparations", "Play", "Probability", "Protease Inhibitor", "Protein Analysis", "Proteins", "Pseudomonas aeruginosa", "RNA", "Reproducibility", "Research Project Summaries", "Roentgen Rays", "Role", "SARS-CoV-2 inhibitor", "SH2D3C gene", "Specificity", "Spectrum Analysis", "Structure", "System", "Technology", "United States National Institutes of Health", "Variant", "Viral", "Virus", "Virus Replication", "X-Ray Crystallography", "biophysical chemistry", "cost effective", "design", "drug discovery", "flexibility", "human pathogen", "influenza infection", "influenzavirus", "inhibitor therapy", "innovation", "insight", "microorganism", "novel", "novel therapeutics", "pathogenic bacteria", "priority pathogen", "programs", "protein structure prediction", "receptor", "reconstitution", "therapeutic development", "vaccine development" ], "approved": true } }, { "type": "Grant", "id": "9932", "attributes": { "award_id": "5R35GM142481-02", "title": "Immunological Endotyping of Chronic Critical Illness after Severe Trauma or Sepsis", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 22300, "first_name": "XIAOLI", "last_name": "Zhao", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-08-15", "end_date": "2026-07-31", "award_amount": 388750, "principal_investigator": { "id": 24334, "first_name": "Scott Charles", "last_name": "Brakenridge", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 159, "ror": "https://ror.org/00cvxb145", "name": "University of Washington", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 159, "ror": "https://ror.org/00cvxb145", "name": "University of Washington", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "Severe traumatic injury and sepsis are acute pro-inflammatory insults that trigger a “genomic and cytokine storm” by the host innate immune response that can result in multiple organ failure (MOF). Whereas many patients previously succumbed to early refractory MOF, progressive advancements in resuscitation and organ support have led to an increasing number of patients surviving to enter a state of chronic critical illness (CCI), defined as a patient with an extended intensive care unit (ICU) stay and non-resolving organ dysfunction. Currently, as many as 25% of trauma and 40% of septic patients in the ICU develop CCI. In addition to a prolonged hospital course, these ICU “survivors” have recurrent infections, are unable to physically rehabilitate, and are frequently discharged to high-resource care facilities with dismal long-term outcomes. Two clinical manifestations dominate the course of the CCI phenotype: 1) recurrent nosocomial and post-discharge infections indicative of a state of chronic immunosuppression, and 2) acute muscle wasting, weakness and physical debilitation indicative of persistent inflammation. There is an expanding body of evidence that an underlying syndrome of persistent inflammation, immunosuppression and catabolism (PICS) is a key mechanistic driver of CCI. We hypothesize that PICS is its own unique immunological endotype independent of the index event, and is the shared mechanistic pathway leading from either trauma or sepsis to the clinical phenotype of CCI. This maladaptive host response is sustained by the ongoing release of endogenous alarmins (DAMPs) associated with end-organ injury, as well as microbial products from primary/secondary infections (PAMPs). This failure to return to immunologic homeostasis also drives the persistent organ dysfunction seen in CCI. Muscle, being both clinically relevant and understudied, serves as a novel area of study from the standpoint of inflammation-mediated end- organ injury both as a driver of acute muscle wasting, as well as a potential source of ongoing alarmin production and release. The goals for our laboratory’s research program over the next five years include the following: 1) characterize the heterogeneity of the host response after severe trauma and sepsis by identifying distinct endotypes based on immune trajectory over time, and whether these endotypes are modified by sex, age and ethnicity/race; 2) determine if the PICS endotype is the common mechanistic pathway after trauma or sepsis to the clinical development of CCI; and 3) determine whether muscle inflammation is both a component of chronic end-organ injury, as well as a mediator of systemic inflammation through the systemic release of endogenous alarmins. The proposed work is novel, innovative and vital. There are currently no therapeutic interventions other than supportive therapies for the increasingly common condition of CCI after trauma or sepsis. We believe that only through a complete understanding of the immunological endotype of CCI can effective therapeutic interventions be designed. Focusing on interactions between host immunity and muscle inflammation is a novel, under-explored area of research for the long-term management of severe trauma and sepsis.", "keywords": [ "Acute", "Area", "Catabolism", "Chronic", "Clinical", "Critical Illness", "Ethnic Origin", "Event", "Failure", "Functional disorder", "Genomics", "Goals", "Health care facility", "Heterogeneity", "Homeostasis", "Hospitals", "Immune", "Immune response", "Immunity", "Immunologics", "Immunosuppression", "Infection", "Inflammation", "Inflammatory", "Innate Immune Response", "Intensive Care Units", "Laboratory Research", "Mediating", "Mediator of activation protein", "Multiple Organ Failure", "Muscle", "Muscular Atrophy", "Organ", "Outcome", "Pathway interactions", "Patients", "Phenotype", "Production", "Race", "Recurrence", "Refractory", "Research", "Resources", "Resuscitation", "Role", "Sepsis", "Source", "Supportive care", "Survivors", "Syndrome", "Therapeutic Intervention", "Time", "Trauma", "Trauma patient", "Traumatic injury", "Work", "base", "clinical development", "clinical phenotype", "clinically relevant", "cytokine release syndrome", "design", "indexing", "innovation", "microbial", "mortality", "novel", "organ injury", "programs", "recurrent infection", "secondary infection", "septic patients", "severe injury", "sex", "systemic inflammatory response", "therapeutically effective" ], "approved": true } }, { "type": "Grant", "id": "9922", "attributes": { "award_id": "5R35GM142863-02", "title": "Advancing Methods in Infectious Diseases Models: Incorporating Structural Causes", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 12060, "first_name": "Han", "last_name": "Nguyen", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-08-15", "end_date": "2026-07-31", "award_amount": 389962, "principal_investigator": { "id": 22797, "first_name": "Nadia Natasha", "last_name": "Abuelezam", "orcid": null, "emails": "[email protected]", "private_emails": null, "keywords": "[]", "approved": true, "websites": "[]", "desired_collaboration": "", "comments": "", "affiliations": [ { "id": 425, "ror": "https://ror.org/02n2fzt79", "name": "Boston College", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 425, "ror": "https://ror.org/02n2fzt79", "name": "Boston College", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "This research program aims to develop novel modeling methods, tools, and guidelines to incorporate racialized lived experiences into mathematical models of infectious disease transmission by explicitly modeling structural drivers of racial disparities in infectious disease exposure, susceptibility and severity, and consequences. In particular, this research will intentionally engage with geographic disparities in the United States through geographic information systems (GIS) coded data to highlight the importance of social context and determinants across the life course to the transmission of infectious diseases. We will employ systems science to analyze in silico simulations and post-hoc data analysis of simulation output to understand the structural drivers of infectious disease disparities. In silico simulation allows for the development of synthetic populations that represent individuals and households (and their characteristics) within a particular geographic area. We plan to modify the model structure to explore the impact and specificity gained by adding a variety of model characteristics, including stochasticity, natural history, and environmental influence. We then aim to perform comprehensive sensitivity analyses accounting for social and political context and the incorporation of multiple interacting factors that may help identify patterns in spread of particular disease types. Ultimately, the goal of the in silico simulations is to mathematically link policy effects to health outcomes through racialized lived experiences (represented and parameterized as agent characteristics). While the modeling frame will be flexible, we will use data on SARS-CoV-2 and influenza as two examples to demonstrate the feasibility of the methods we develop. The results from this work will allow us to develop policy recommendations for structural interventions to reduce racial disparities in infectious disease outcomes. Incorporating structural interventions into the model structure will require flexibility to account for the interference and feedback with individual behaviors. The structural interventions we plan to examine using in silico simulations include eliminating residential segregation, increasing accessibility to stable housing, reducing income inequality, and distribution of healthy food choices represented by real-world programs across the United States. This research will lay the groundwork to inform ongoing control of existing and emerging infectious disease pathogens and prevent the unequal health- and cost-related burdens on communities of color.", "keywords": [ "2019-nCoV", "Accounting", "Behavior", "Characteristics", "Code", "Color", "Communicable Diseases", "Communities", "Data", "Data Analyses", "Development", "Disease", "Disease Outcome", "Emerging Communicable Diseases", "Feedback", "Geographic Information Systems", "Geographic Locations", "Goals", "Guidelines", "Health", "Health Care Costs", "Health Food", "Household", "Housing", "Income", "Individual", "Inequality", "Influenza", "Intervention", "Life Cycle Stages", "Link", "Mathematics", "Methods", "Modeling", "Natural History", "Outcome", "Output", "Pattern", "Policies", "Politics", "Population", "Predisposition", "Research", "Science", "Severities", "Social Environment", "Specificity", "Structural Models", "Structure", "System", "Testing", "United States", "Work", "disease disparity", "disease transmission", "experience", "flexibility", "geographic disparity", "in silico", "infectious disease model", "mathematical model", "novel", "pathogen", "policy recommendation", "prevent", "programs", "racial disparity", "residential segregation", "simulation", "social", "social determinants", "tool" ], "approved": true } }, { "type": "Grant", "id": "11605", "attributes": { "award_id": "5R35GM144124-02", "title": "MECHANISMS AND MACROMOLECULAR INTERACTIONS UNDERLYING CELLULAR RESPONSES TO STRESS SIGNALS", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 27542, "first_name": "Marc", "last_name": "Rigas", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2022-04-01", "end_date": "2027-03-31", "award_amount": 398750, "principal_investigator": { "id": 22608, "first_name": "Alexandra M.", "last_name": "Deaconescu", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 222, "ror": "https://ror.org/05gq02987", "name": "Brown University", "address": "", "city": "", "state": "RI", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 222, "ror": "https://ror.org/05gq02987", "name": "Brown University", "address": "", "city": "", "state": "RI", "zip": "", "country": "United States", "approved": true }, "abstract": "Proteins carrying out DNA repair, replication and transcription, processes essential for the stable transmission and expression of genomic information, share the same track – the DNA – and require delicate coordination to achieve their function. Often, regulation of these processes occurs at the level of targeting or well-timed recruitment, but also catalysis and even turnover of the factor in question. We will address these three principal modalities of regulation in the context of bacterial responses to stress signals. Our questions and hypotheses are grouped into two large areas, (1) regulation of the general stress response mediated by the promoter specificity subunit RpoS; this is exemplary of a general stress response mechanism that affect transcription initiation, and (2) specific responses to DNA damage such as subpathways of nucleotide excision repair; these are exemplary of how the DNA damage response interfaces with transcription elongation, termination as well as replication. The principal questions that will be addressed by my research plan are: A. How are activating and inhibitory regulatory inputs integrated to tune the RpoS core pathway and globally reprogram transcription in response to an adverse environment? How does the ClpXP adaptor RssB and stress-specific ClpXP anti-adaptors tune the proteolysis of RpoS in a stress-specific manner? B. What are the mechanisms for preferential recruitment of the NER machinery to specific lesions, or to the template strand, directly read by RNA polymerase? How is the availability of early NER factors regulated by proteolysis in the context of DNA damage and transcription-coupled DNA repair? How and when do transcription-repair coupling factors collaborate with key players in the SOS response to promote mutagenesis? Can we leverage these mechanisms towards developing novel anti-evolution drugs for combination therapies against infection with diverse pathogens? Previous work has already allowed us to build a critical collection of reagents and expertise in the structural biology and biochemistry of transcription-coupled repair and RpoS biology. This gives us now an excellent entry point for a mechanistic dissection of the processes listed above and the development of novel antimicrobial strategies. The significance of our work is thus not only fundamental and conceptual in nature, but has immediate applications in controlling the worldwide public health crisis of antimicrobial resistance, particularly in the age of the COVID-19 pandemic.", "keywords": [ "Address", "Affect", "Age", "Antibiotics", "Antimicrobial Resistance", "Area", "Bacteria sigma factor KatF protein", "Biology", "COVID-19 pandemic", "Catalysis", "Collaborations", "Collection", "Combination Drug Therapy", "Coupled", "Coupling", "DNA", "DNA Damage", "DNA Repair", "DNA-Directed RNA Polymerase", "Development", "Dissection", "Environment", "Evolution", "Genetic Transcription", "Genomics", "Infection", "Lesion", "Mediating", "Modality", "Molecular Evolution", "Mutagenesis", "Nature", "Nucleotide Excision Repair", "Organism", "Pathway interactions", "Process", "Proteins", "Proteolysis", "Public Health", "Reagent", "Regulation", "Research", "SOS Response", "Signal Transduction", "Specificity", "Stress", "Structural Biochemistry", "Transcription Elongation", "Transcription Initiation", "Transcription-Coupled Repair", "Work", "antimicrobial", "biological adaptation to stress", "cross immunity", "novel", "pathogen", "programs", "promoter", "recruit", "repaired", "response", "stressor", "structural biology", "transmission process" ], "approved": true } }, { "type": "Grant", "id": "10893", "attributes": { "award_id": "5R35GM144147-02", "title": "Photonics-based Fluorescence Imaging for Research, Diagnostics, and Pathology", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 23422, "first_name": "ALVIN TIEN-WEI", "last_name": "Yeh", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2022-02-01", "end_date": "2027-01-31", "award_amount": 347625, "principal_investigator": { "id": 23686, "first_name": "Joseph R.", "last_name": "LAKOWICZ", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 793, "ror": "", "name": "UNIVERSITY OF MARYLAND BALTIMORE", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 793, "ror": "", "name": "UNIVERSITY OF MARYLAND BALTIMORE", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "- Photonics-based Fluorescence Imaging for Research, Diagnostics and Pathology During the past several decades fluorescence detection has become a central technology throughout the biosciences. The basic applications include studies of biomolecule function, properties of cell membranes and localization of target molecules in cells. The more clinical applications include immunoassays, flow cytometry, point-of-care diagnostics, genetic testing, and cell imaging by fluorescence microscopy. Fluorescence is expanding to include in-vivo measurements on brain tissues using multi-photon excitation. While fluorescence technology has advanced, it has not kept pace with the advances in electronics and array detectors (cameras). The sizes of optical components such as lenses and filters are much larger than electronic components as can be seen from a cell phone with millions of transistors, but only one or two lenses in a cell phone. This mismatch in size cannot be circumvented by making smaller lenses, filters or fiber optics. These optical components require dimensions of many wavelengths to manipulate freely propagating light. We propose to overcome this limitation by using fluorophores positioned within sub-wavelength near-field distances from the plasmonic, photonic or plasmonic multi-layer structures (MLS). We are NOT proposing to use the fluorophores as electronic components, but rather to directly couple their emission into CMOS imaging detectors with MLSs without free-space propagation of light. The MLS controls the propagation of optical energy, can separate wavelengths and can direct the energy (coupled photons) towards nearby detectors. This concept will provide the basis for new devices for research and medicine. To demonstrate the usefulness of these devices we have established collaborations with senior faculty in the School of Medicine. These collaborations include detection of weak binding in drug discovery or high throughput screening (HTS) because much of the HTS is used with drug fragments which bind weakly to target molicules. Most of the MLS retain spatial information in the x-y plane which allows either ensemble or virus particle counting assays for HIV and the Covid-19 virus SARS-CoV-2. The wide field of view will allow whole slide imaging of pathology specimens. Our goal is to develop this new area of near-field effects in fluorescence, with easy to fabricate strruvtures, to enable a new generation of instruments and devices for fluorescence detection in research, sensing and imaging.", "keywords": [ "2019-nCoV", "Area", "Binding", "Biological Assay", "Biological Sciences", "Cell membrane", "Cells", "Cellular Phone", "Centenarian", "Collaborations", "Complex", "Coupled", "Detection", "Devices", "Diagnostic", "Dimensions", "Electronics", "Fiber Optics", "Flow Cytometry", "Fluorescence", "Fluorescence Microscopy", "Generations", "Goals", "HIV", "Image", "Imaging Device", "Immunoassay", "Light", "Measurement", "Medicine", "Microscope", "Optics", "Pathology", "Pharmaceutical Preparations", "Photons", "Positioning Attribute", "Property", "Research", "Slide", "Specimen", "Structure", "Technology", "Transistors", "Virion", "Virus", "base", "brain tissue", "cellular imaging", "clinical application", "consumer product", "detector", "drug discovery", "fluorescence imaging", "fluorescence microscope", "fluorophore", "genetic testing", "high throughput screening", "imaging detector", "in vivo", "instrument", "lens", "medical schools", "multi-photon", "optical fiber", "pathology imaging", "photonics", "plasmonics", "point-of-care diagnostics", "senior faculty", "whole slide imaging" ], "approved": true } } ], "meta": { "pagination": { "page": 1384, "pages": 1442, "count": 14420 } } }