Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1384&sort=end_date
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=end_date", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1419&sort=end_date", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1385&sort=end_date", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1383&sort=end_date" }, "data": [ { "type": "Grant", "id": "15580", "attributes": { "award_id": "5R01MH132730-02", "title": "Racial discrimination, Intergenerational Cultural Conflict and Asian American Mental Health", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Mental Health (NIMH)" ], "program_reference_codes": [], "program_officials": [ { "id": 25563, "first_name": "Alexander M", "last_name": "Talkovsky", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-11-16", "end_date": "2028-10-31", "award_amount": 680848, "principal_investigator": { "id": 29176, "first_name": "YOONSUN", "last_name": "CHOI", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 289, "ror": "https://ror.org/024mw5h28", "name": "University of Chicago", "address": "", "city": "", "state": "IL", "zip": "", "country": "United States", "approved": true }, "abstract": "PROJECT SUMMARY: The high rates and upward trend of mental health (MH) problems among young Asian Americans (AAs) are disturbing. Despite mounting evidence of MH crisis, AAs are severely understudied, exacerbating health disparities. Spikes in sociopolitical tensions and racial hostility in recent years may explain the upsurge of the problems. Young AAs are under great acculturative as well as minority stress, including being the frequent victims of hate crimes, experiencing harmful objectification by the majority and other minority groups, and having their American identities questioned. This stressful environment has been aggravated by the COVID-19 pandemic, which has provoked an unprecedented surge in anti-Asian racism and bigotry. There is a particularly pressing need for young AAs to identify ways to navigate these multifold pressures. This proposed study will extend an existing, highly successful longitudinal study of young AAs. The Midwest Longitudinal Study of Asian American Families (MLSAAF) is an ongoing survey of Filipino American (FA) and Korean American (KA) families (786 youth and their parents; MAGE of youth = 15 at Wave 1 in 2014). Wave 4 in 2021 collected data from 615 young adults (YAs) (MAGE=21.5; 78% retention). The MLSAAF has substantiated a troubling upward trend in MH struggles from 2014 to 2021 as participants transitioned to early young adulthood (YAH). We also uncovered racial discrimination and intergenerational cultural conflict (ICC) in the family as the etiology of this upsurge of problems. Minority and acculturative stresses are expected to amplify as YAs build careers and families of their own. AA families remain interdependent during YAH, with unwavering expectations of familism, conceivably prolonging ICC among AA YAs. By adding 3 waves, the proposed study will leverage the rich and rare MLSAAF data to follow the original samples from adolescence (ADOL) into their twenties to disentangle the complex and dynamic effects of family process, minority stress, and acculturation across the critical stages of YAH, including such pivotal outcomes as education, employment, marriage, and parenthood. Biomarkers (cortisol, C-reactive protein, and sleep) are added to investigate physiological damage of chronic stress from racial/cultural minority status. The inclusion of biomarkers will significantly enhance our capacity to more accurately assess biological, physical, and psychological harms of chronic stress that individuals may be unaware of. This study will (1) determine the trajectory and etiology of MH and physical health among young AAs as they transition from early ADOL to YAH. We will test (a) how AA family process (e.g., harmful vs. beneficial practices) is concurrently and longitudinally associated with ICC and the MH/health outcomes and (b) how racial discriminations are concurrently and longitudinally associated with poor outcomes, (2) investigate how bicultural competence mitigates the negativity of chronic psychosocial stressors (i.e., ICC and discrimination) and (3) to examine the associations in Aims 1 and 2 with biomarkers as outcome measures and to identify harms of chronic stress that self-report measures may not capture.", "keywords": [ "19 year old", "Acculturation", "Adolescence", "Adolescent", "American", "Anxiety", "Area", "Asian", "Asian Americans", "Biological", "Biological Markers", "C-reactive protein", "COVID-19 pandemic", "Cause of Death", "Chicago", "Child", "Chronic", "Chronic stress", "Complex", "Conflict (Psychology)", "Data", "Data Set", "Databases", "Development", "Diagnosis", "Discrimination", "Distress", "Education", "Employment", "Environment", "Ethnic Origin", "Etiology", "Evidence based intervention", "Family", "Family Process", "Feeling suicidal", "Filipino American", "Foundations", "Funding", "Gender", "Health", "Home", "Hostility", "Hydrocortisone", "Immigrant family", "Individual", "Intervention", "Korean American", "Longitudinal Studies", "Major Depressive Disorder", "Major Mental Illness", "Marriage", "Measures", "Mental Depression", "Mental Health", "Midwestern United States", "Minority", "Minority Groups", "Minority Status", "National Institute of Child Health and Human Development", "Occupations", "Onset of illness", "Outcome", "Outcome Measure", "Parents", "Participant", "Pattern", "Personal Satisfaction", "Persons", "Physiological", "Politics", "Positioning Attribute", "Psyche structure", "Public Health", "Race", "Reporting", "Risk Behaviors", "Sampling", "Secure", "Sleep", "Socialization", "Stereotyping", "Stress", "Suicide", "Surveys", "Testing", "Violence", "Youth", "affection", "age group", "anti-Asian", "career", "cultural competence", "early adolescence", "ethnic identity", "evidence base", "expectation", "experience", "hate crimes", "health disparity", "improved", "intergenerational", "metropolitan", "minority stress", "minority stressor", "pandemic disease", "perceived discrimination", "perceived stress", "physical conditioning", "post-COVID-19", "pressure", "promote resilience", "psychologic", "psychosocial stressors", "public health relevance", "racial discrimination", "racial minority", "racial population", "racism", "response", "stressor", "suicidal", "trend", "young adult" ], "approved": true } }, { "type": "Grant", "id": "15585", "attributes": { "award_id": "5R01AI179720-02", "title": "Functional Viromics of Betacoronavirus Entry", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 27781, "first_name": "Mary Katherine Bradford", "last_name": "Plimack", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-11-16", "end_date": "2028-10-31", "award_amount": 354008, "principal_investigator": { "id": 29195, "first_name": "Barbara A.", "last_name": "Han", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 29196, "first_name": "Michael", "last_name": "Letko", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 306, "ror": "https://ror.org/05dk0ce17", "name": "Washington State University", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "After the severe acute respiratory coronavirus (SARS-CoV) emerged in China in 2002, the virus was traced back to animal markets and several genetically related viruses were identified in bats. This early work into coronavirus zoonosis and the concomitant rise of next generation sequencing technologies in the early 2000’s helped initiate global research efforts to identify viruses circulating in wildlife. The genomes for tens of thousands of novel animal viruses have now been sequenced and deposited in online repositories. Coronaviruses are abundant in mammals and birds and comprise approximately 25% of all bat viruses discovered to date. The highly pathogenic human coronaviruses, SARS-CoV, and middle east respiratory syndrome coronavirus (MERS-CoV) are only representative members of their respective sarbeco- and merbeco- subgenera, which encompass hundreds of related viruses found in bats and other wildlife, worldwide. Unfortunately, because there are few tools available for researchers to study uncharacterized animal viruses, virus discovery studies rarely isolate viruses under laboratory conditions or perform experiments beyond genetic sequencing, leaving some of the most essential questions about these viruses – including if they have the potential to infect humans – unanswered. An improved understanding for what species these viruses can infect and how they invade the cells of their hosts is essential for future pandemic preparedness. The most significant species barrier for the coronaviruses that have transmitted to humans is at the level of cell entry and studies have shown that overcoming this barrier allows for coronaviruses to replicate in cells from diverse species. To invade cells, the “spike” glycoprotein on the surface of viral particles binds to host cell receptor molecules. The receptor binding domain (RBD) is a small region on the distal tip of the spike protein, capable of folding independently of spike and contains all amino acids that contact the host receptor. We previously developed “SarbecoType” – a BSL2-compatible, viral pseudotype-based platform to functionally screen the cell entry properties of the RBD from any sarbecovirus. This approach is highly cost- efficient and scalable, requiring synthesis of only a small portion of the spike gene, and has allowed us to characterize the cell entry phenotypes of approximately 95% of all published sarbecoviruses. This dataset identified multiple clades of sarbecovirus RBDs that vary in their zoonotic properties for humans, and has formed a foundational basis for ongoing universal sarbecovirus design. Therefore, we hypothesize uncharacterized coronaviruses pose a threat to humans. Here we propose to functionally screen the much larger and diverse group of merbecoviruses with similar methods (I.e., “MerbecoType”) and use this entry data to predict the entry capabilities of novel sarbeco- and merbeco-virus sequences.", "keywords": [ "2019-nCoV", "Amino Acids", "Animals", "Back", "Binding", "Birds", "Cells", "China", "Chiroptera", "Collaborations", "Computer Models", "Computing Methodologies", "Coronavirus", "Data", "Data Set", "Dependence", "Deposition", "Disease Outbreaks", "Distal", "Genes", "Genetic", "Genome", "Geography", "Glycoproteins", "Human", "Infection", "Invaded", "Laboratories", "Length", "Mammals", "Marketing", "Merbecovirus", "Methods", "Middle East Respiratory Syndrome Coronavirus", "Modeling", "Molecular", "Pathogenicity", "Peptide Hydrolases", "Phenotype", "Population", "Property", "Proteins", "Publishing", "Receptor Cell", "Reporter", "Research", "Research Personnel", "Resistance", "Risk", "Route", "SARS coronavirus", "Sarbecovirus", "Silent Mutation", "Surface", "System", "Technology", "Testing", "Training", "Vaccines", "Variant", "Viral", "Virus", "Virus Receptors", "Work", "Zoonoses", "betacoronavirus", "coronavirus receptor", "cost", "cost efficient", "cross-species transmission", "design", "experimental study", "follow-up", "future pandemic", "gene synthesis", "human coronavirus", "improved", "in silico", "machine learning model", "member", "next generation", "next generation sequencing", "novel", "novel coronavirus", "online repository", "pandemic preparedness", "particle", "preference", "receptor", "receptor binding", "screening", "therapy resistant", "tool", "transmission process", "trend", "universal coronavirus vaccine", "virome" ], "approved": true } }, { "type": "Grant", "id": "15809", "attributes": { "award_id": "1F30AI194770-01", "title": "Impact of Natural Infection on the Baseline Immune States in Humans", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 32556, "first_name": "TIMOTHY A", "last_name": "GONDRE-LEWIS", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-11-01", "end_date": "2028-10-31", "award_amount": 34558, "principal_investigator": { "id": 44212, "first_name": "Yona", "last_name": "Lei", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3363, "ror": "", "name": "YALE UNIVERSITY", "address": "", "city": "", "state": "CT", "zip": "", "country": "United States", "approved": true }, "abstract": "Influenza is a year-round public health burden, causing millions of severe illnesses and hundreds of thousands of respiratory deaths globally. A key challenge in developing more effective vaccines lies in the inherent variability of the human immune system, as vaccine responses are highly variable across individuals, with many failing to develop adequate protective immunity. Low vaccine responsiveness has been associated with specific pre- vaccination baseline immune states. The baseline immune state of an individual determines their immune function and response. We and others have linked inter-individual variations in vaccination outcomes to molecular and cellular immune components that encode the baseline state. Our group previously showed that high vaccine responsiveness is associated with a “naturally adjuvanted” baseline state characterized by enhanced innate immune response potential, a finding supported by corresponding differences in stimulation responses of immune cells from high and low vaccine responders in vitro. We also found that clinically healthy males recovered from mild COVID-19 exhibited a more “poised” baseline state and stronger immune responses to subsequent influenza vaccination. These studies suggest that variations in baseline immune states contribute to heterogenous responses to vaccination, and that prior exposures may establish new baseline states that impact future responses in an antigen-agnostic manner. It remains unclear how infection alters an individual's baseline state over time, how these changes vary across individuals, and if they have functional consequences. Using longitudinal samples from a household cohort that allows control for environmental confounders, and using influenza infection as a model, my proposal aims to address these gaps to better understand the functional impact of infection on baseline immune states. Given the antigen-nonspecific nature of innate immune cells, understanding how infection impacts their function is a key to revealing potential underlying mechanisms. I hypothesize that influenza infection induces durable antigen-agnostic transcriptional and epigenetic changes that give rise to enhanced innate immune response potential. Aim 1 will assess the impact of infection on baseline immune states and innate cell response capacity. Through single-cell multimodal immune profiling, I will assess infection-induced transcriptional and epigenetic changes in peripheral immune cells. Using the same samples, I will examine innate response capacity to in vitro stimulation. Aim 2 will elucidate how infection-induced durable changes mechanistically drive innate cell responses to stimulation. I will implement a causal network inference approach to infer immune determinants of response capacity, followed by experimental validation to establish causality. This work will advance our understanding of infection-induced antigen-agnostic immune reprogramming, potentially revealing key drivers of human immune variation and strategies to modulate baseline states for improving vaccination outcome. Rigorous scientific training will be guided by mentors with experimental and computational expertise, complemented by longitudinal clinical and professional skill development.", "keywords": [ "Address", "Adjuvant", "Age", "Antibody titer measurement", "Antigens", "B-cell receptor repertoire sequencing", "Biological Assay", "COVID-19", "Cells", "Cellular Indexing of Transcriptomes and Epitopes by Sequencing", "Cessation of life", "Chromatin", "Clinical", "Computer Models", "Data", "Effectiveness", "Epigenetic Process", "Etiology", "Exhibits", "Future", "Genetic Transcription", "Goals", "Household", "Human", "Immune", "Immune response", "Immune system", "Immunity", "Immunologic Stimulation", "Immunologics", "Immunology", "In Vitro", "Individual", "Infection", "Influenza", "Influenza vaccination", "Innate Immune Response", "Link", "Lipopolysaccharides", "Mentors", "Modeling", "Molecular", "Nature", "Output", "Peripheral", "Peripheral Blood Mononuclear Cell", "Public Health", "Role", "Same-sex", "Sampling", "Shapes", "Signal Pathway", "Signal Transduction", "Study Subject", "System", "T-Lymphocyte", "Time", "Training", "Translating", "Transposase", "Vaccination", "Vaccine Design", "Vaccines", "Validation", "Variant", "Virus Diseases", "Work", "adaptive immunity", "clinical application", "cohort", "design", "immune function", "implementation strategy", "improved", "influenza infection", "influenza virus vaccine", "innate immune function", "insight", "inter-individual variation", "male", "multimodality", "novel vaccines", "pathogen", "respiratory", "response", "seasonal influenza", "sex", "single-cell RNA sequencing", "skill acquisition", "skills", "universal influenza vaccine", "vaccination outcome", "vaccine response" ], "approved": true } }, { "type": "Grant", "id": "14725", "attributes": { "award_id": "1R01MH135267-01", "title": "Maturation of Social and Non-Social Reward Processing in the Adolescent Amygdala and Orbitofrontal Cortex", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Mental Health (NIMH)" ], "program_reference_codes": [], "program_officials": [ { "id": 22777, "first_name": "Andrew Lee", "last_name": "Breeden", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-02-20", "end_date": "2028-11-30", "award_amount": 587651, "principal_investigator": { "id": 31413, "first_name": "Steve Wohn Chul", "last_name": "Chang", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 31414, "first_name": "Katalin M", "last_name": "Gothard", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 438, "ror": "https://ror.org/03m2x1q45", "name": "University of Arizona", "address": "", "city": "", "state": "AZ", "zip": "", "country": "United States", "approved": true }, "abstract": "Adolescence is a time of substantial development attributed to the maturation of brain circuits that underlie the acquisition of new cognitive, emotional, and social skills. It is also a time of maximum vulnerability for mental disorders. In the past decade, the incidence of anxiety, depression, and suicide increased by ~60% in adolescents, remarkably more in females than in males. The social isolation during the COVID-19 pandemic added to the severity of the national and international statistics. To fully address the current youth mental health crisis, we need to understand how and why the dramatic reorganization of the adolescent brain contributes to the increased vulnerability to mental disorders. The studies proposed here rest on the assumption that the remodeling of the reward circuits of the brain creates the shared foundation of cognitive, affective, and social maturation during adolescence. Our multifaceted project addresses foundational gaps in our knowledge on how reward-driven motivational states inform adolescent behaviors such as risk-taking, pleasure-seeking, impulsivity, and a range of emotional responses to challenges of the social environment. We designed a within-subject, longitudinal study that spans the 2.5 - 3-year duration of adolescence in non-human primates. During this period, we will obtain repeated samplings of neurophysiological data recorded from the amygdala and orbitofrontal cortex in the context of the same behavioral tasks. In parallel, we will longitudinally monitor morphometric and microstructural changes in the gray and white matter of the brain through serial MRI scans, complemented by physical and hormonal measures of pubertal maturation. The three specific aims address the neural basis of three different aspects of reward processing in the subcircuit of the amygdala and orbitofrontal cortex. First, we will use a delay discounting task to determine the cellular and circuit level changes that underlie the increasing tolerance (or lack thereof) for delayed rewards. Second, we use a social reward-allocation task to test the neural underpinning of social reward processing in a self-oriented and an other-oriented social frame of reference. Finally, we will determine where and how social status is processed in the adolescent brain. Understanding social status relies on the ability to form abstract representations and is also a prerequisite for the successful integration of the individual into a hierarchical adult social group. The team, with combined expertise in human and non-human primate social behavior, neurophysiology, neuroimaging, and endocrinology, will apply conceptually and technically innovative approaches to generate unique and translational data, at both cellular and circuit levels, that account for the emerging cognitive, affective, and social skills acquired during adolescence.", "keywords": [ "Address", "Adolescence", "Adolescent", "Adolescent Behavior", "Adult", "Affective", "Amygdaloid structure", "Anxiety", "Area", "Behavior", "Behavior monitoring", "Behavioral", "Benefits and Risks", "Brain", "COVID-19 pandemic", "Cells", "Cognitive", "Data", "Decision Making", "Development", "Disparity", "Economics", "Education", "Emotional", "Emotional Bonds", "Endocrine", "Endocrinology", "Female", "Foundations", "Frequencies", "Glean", "Goals", "Hormonal", "Human", "Impulsivity", "Incidence", "Individual", "International", "Joints", "Knowledge", "Longitudinal Studies", "MRI Scans", "Macaca", "Measures", "Mental Depression", "Mental Health", "Mental disorders", "Modeling", "Monitor", "Monkeys", "Motivation", "Neurons", "Outcome", "Partner in relationship", "Peer Group", "Performance", "Population", "Prefrontal Cortex", "Process", "Property", "Psychological reinforcement", "Puberty", "Race", "Rest", "Rewards", "Risk", "Risk Estimate", "Risk Taking", "Saccades", "Sampling", "Serial Magnetic Resonance Imaging", "Series", "Severities", "Social Behavior", "Social Environment", "Social Interaction", "Social isolation", "Social status", "Stress", "Suicide", "Testing", "Time", "United States National Institutes of Health", "Youth", "design", "discounting", "emotion regulation", "gaze", "gray matter", "innovation", "insight", "joint attention", "male", "multidisciplinary", "myelination", "neural", "neural circuit", "neuroimaging", "neurophysiology", "nonhuman primate", "nutrition", "peer", "pleasure", "response", "reward processing", "sex", "skill acquisition", "social", "social group", "social skills", "statistics", "white matter" ], "approved": true } }, { "type": "Grant", "id": "14740", "attributes": { "award_id": "1R01AI181955-01", "title": "Structural and functional definition of human astrovirus-receptor interactions", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 6817, "first_name": "Rodolfo M.", "last_name": "Alarcon", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-01-19", "end_date": "2028-11-30", "award_amount": 665809, "principal_investigator": { "id": 31411, "first_name": "Megan T", "last_name": "Baldridge", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 827, "ror": "", "name": "WASHINGTON UNIVERSITY", "address": "", "city": "", "state": "MO", "zip": "", "country": "United States", "approved": true }, "abstract": "Human astroviruses (HAstVs) are a global cause of pediatric gastroenteritis, and can cause disseminated infection in immunocompromised hosts. Seroprevalence studies indicate almost universal HAstV infection during childhood. Despite their clinical importance, HAstVs are highly understudied. Little is known about the host factors needed for infection or their mechanisms of viral entry into cells, and no proteinaceous viral receptor has been identified to date. Beyond providing critical insights into virus-host interactions, identification of host proteins sufficient and/or necessary for HAstV infection is key for creating small animal models permissive to infection and to revealing antiviral strategies to combat infection. Leveraging both genome-wide knock-out CRISPR and surfaceome-specific CRISPR activation screening, novel proteinaceous host receptors for HAstV were identified. These factors, neonatal Fc receptor (FcRn) and dipeptidyl peptidase 4 (DPP4), have also been implicated in viral infection for echovirus and coronavirus infection respectively. Both were confirmed as necessary for in vitro HAstV infection of Caco2 cells and as sufficient to permit HAstV infection of normally non-permissive human cells when overexpressed. Additionally, use of biolayer interferometry confirmed direct physical interactions between both FcRn and DPP4 with the HAstV capsid. These preliminary data serve as the critical foundation for the extensive structural and functional studies proposed here. In Aim 1, the specific protein domains and amino acid residues of FcRn and DPP4 that functionally interact with the HAstV capsid will be identified, as will the viral capsid residues critical for binding these host factors. Cryogenic electron microscopy will be leveraged to reveal how binding to these factors affects the HAstV virion. These genetic and biophysical analyses will provide much-needed insight into HAstV entry biology and form the basis of future pharmacological screens for identification of entry inhibitors. In Aim 2, permissive human intestinal enteroid cultures will be used to determine the necessity of identified entry factors for ex vivo HAstV infection. Blocking of infection via addition of soluble entry factors, anti-factor antibodies, inhibitors, and CRISPR-mediated disruption of factors in these cultures will be performed. Additionally, existing mouse models expressing human FcRn and DPP4 will be used to develop mice permissive to HAstV infection and to evaluate whether these factors are critical for murine astrovirus infection. These studies will reveal the species-specificity of receptor use and provide powerful new tools for study of HAstV pathogenesis and immune response as well as for preclinical testing of vaccines and antivirals. The use of numerous orthogonal approaches, including mechanistic studies of critical receptor domains, state-of-the-art structural techniques, and physiologically-relevant models, will yield a comprehensive picture of how these novel entry factors promote HAstV infection.", "keywords": [ "Affect", "Amino Acids", "Animal Model", "Anti-viral Agents", "Anti-viral Therapy", "Antibodies", "Astrovirus", "Binding", "Biology", "CRISPR screen", "CRISPR-mediated transcriptional activation", "Caco-2 Cells", "Capsid", "Cell Culture Techniques", "Cell Line", "Cells", "Childhood", "Clinical", "Clustered Regularly Interspaced Short Palindromic Repeats", "Colon Adenocarcinoma", "Complementary DNA", "Coronavirus Infections", "Cryoelectron Microscopy", "Data", "Development", "Dipeptidyl Peptidases", "Dipeptidyl-Peptidase IV", "Echo Viruses", "Echovirus Infections", "Ectopic Expression", "Encephalitis", "FDA approved", "Fc Receptor", "Foundations", "Future", "Gastroenteritis", "Gene Knock-Out Model", "Generations", "Genes", "Goals", "Human", "Immune response", "Immunocompromised Host", "In Vitro", "Individual", "Infection", "Infection prevention", "Innate Immune Response", "Integration Host Factors", "Interferometry", "Intestines", "Knock-in", "Knock-out", "Knowledge", "Maps", "Mediating", "Meningitis", "Middle East Respiratory Syndrome Coronavirus", "Modeling", "Molecular", "Mus", "Norovirus", "Pathogenesis", "Physiological", "Preclinical Testing", "Proteins", "RNA Viruses", "Research", "Resolution", "Role", "Rotavirus", "Seroprevalences", "Species Specificity", "Stomach", "Structure", "System", "Techniques", "Technology", "Tertiary Protein Structure", "Testing", "Transgenic Organisms", "Tropism", "Vaccines", "Viral", "Viral Gastroenteritis", "Virion", "Virus", "Virus Diseases", "Virus Receptors", "adaptive immune response", "biophysical analysis", "cell immortalization", "combat", "fighting", "flu", "genetic analysis", "genome-wide", "human model", "in vivo", "inhibitor", "innate immune pathways", "insight", "mortality", "mouse model", "neonatal Fc receptor", "novel", "overexpression", "permissiveness", "pharmacologic", "receptor", "receptor binding", "receptor expression", "receptor function", "reverse genetics", "screening", "tool", "vaccine evaluation", "virus host interaction" ], "approved": true } }, { "type": "Grant", "id": "14760", "attributes": { "award_id": "1K24HL168225-01A1", "title": "Mentoring and Patient-Oriented Research in Clinical Informatics and Data Science", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Heart Lung and Blood Institute (NHLBI)" ], "program_reference_codes": [], "program_officials": [ { "id": 31460, "first_name": "BEENA G", "last_name": "Sood", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-12-01", "end_date": "2028-11-30", "award_amount": 125901, "principal_investigator": { "id": 8404, "first_name": "Tellen", "last_name": "Bennett", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 784, "ror": "https://ror.org/02hh7en24", "name": "University of Colorado Denver", "address": "", "city": "", "state": "CO", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 784, "ror": "https://ror.org/02hh7en24", "name": "University of Colorado Denver", "address": "", "city": "", "state": "CO", "zip": "", "country": "United States", "approved": true }, "abstract": "This K24 mid-career investigator award in patient-oriented research is to support the mentoring, research, and career development activities of Dr. Tell Bennett. Dr. Bennett is an Associate Professor in the University of Colorado School of Medicine and a practicing pediatric ICU physician and informaticist/data scientist with research concentrations in predictive analytics, electronic health record (EHR) data, and clinical decision support (CDS) tool implementation. He is the Informatics Director for the Colorado Clinical and Translational Sciences Institute (CCTSI) and Vice Chair of Clinical Informatics in the Department of Biomedical Informatics. His combined leadership roles have enabled him to build a rich mentoring environment for patient-oriented informatics research. This K24 application proposes to sustain and grow that mentorship program. He currently mentors clinician-scientists in a variety of clinical fields including intensive care, pharmacy, surgery, endocrinology, malignant hematology, and clinical psychology. The K24 Mentoring Plan aligns with Dr. Bennett’s mission to grow patient-oriented research using informatics and data science methods and tools. The mentoring plan leverages educational, career development, and research support programs available through the CCTSI and the new Department. The K24 Research Plan is to develop and implement machine learning and computational physiology models deployable as EHR-based CDS tools. Dr. Bennett currently leads and mentors projects developing CDS tools in both outpatient and inpatient care settings and in a variety of clinical domains include heart failure, traumatic brain injury, serious bacterial infection and sepsis, COVID- 19, thyroid cancer, and postpartum depression. In this K24, developing CDS tools to improve decision-making and outcomes in children with acute respiratory failure (ARF) is a natural next step in this work. ARF is a common, important, and NIH-relevant condition that causes significant pediatric morbidity and mortality. The aims of the project are to 1) develop and validate a dynamic machine learning-based real-time prediction model for intubation in children with ARF and 2) phenotype current lung injury state in mechanically ventilated children using computational physiology models. These models can be deployed as CDS tools and tested as interventions in future clinical trials to improve patient outcomes. The K24 Career Development Plan includes formal mentorship training and coursework in signal processing and dynamical systems models. This group of skills will make Dr. Bennett a more successful mentor.", "keywords": [ "Acceleration", "Acute respiratory failure", "Address", "Adult", "Ambulatory Care", "Bacteremia", "Bacterial Infections", "Biological Models", "Blood", "Breathing", "COVID-19", "Carbon Dioxide", "Caring", "Cause of Death", "Child", "Childhood", "Childhood Injury", "Clinical", "Clinical Data", "Clinical Informatics", "Clinical Psychology", "Clinical Sciences", "Clinical Trials", "Collaborations", "Colorado", "Critically ill children", "Data", "Data Science", "Data Scientist", "Decision Making", "Development", "Development Plans", "Education", "Electronic Health Record", "Endocrinology", "Environment", "Etiology", "Evaluation", "Excision", "Future", "Goals", "Grant", "Heart failure", "Hematology", "Individual", "Informatics", "Intensive Care", "Intervention", "Intubation", "Lead", "Leadership", "Link", "Machine Learning", "Malignant - descriptor", "Malignant neoplasm of thyroid", "Mechanical ventilation", "Medicine", "Mentors", "Mentorship", "Methods", "Mid-Career Clinical Scientist Award (K24)", "Midcareer Investigator Award in Patient-Oriented Research", "Mission", "Modeling", "Monitor", "Morbidity - disease rate", "National Heart Lung and Blood Institute", "Operative Surgical Procedures", "Outcome", "Patient-Focused Outcomes", "Patients", "Pharmacy facility", "Phenotype", "Physicians", "Physiology", "Postpartum Depression", "Predictive Analytics", "Procedures", "Prospective cohort study", "Registries", "Research", "Research Personnel", "Research Support", "Research Training", "Resources", "Respiratory System", "Risk", "Role", "Scientist", "Sedation procedure", "Sepsis", "Structure", "Testing", "Time", "Training", "Training Programs", "Translating", "Translational Research", "Translations", "Traumatic Brain Injury", "Tube", "United States National Institutes of Health", "Universities", "Ventilator", "Ventilator-induced lung injury", "Work", "biomedical informatics", "career", "career development", "clinical decision support", "design", "dynamic system", "experience", "implementation tool", "improved", "improved outcome", "inpatient service", "investigator training", "lung injury", "machine learning model", "mathematical model", "medical schools", "mid-career faculty", "mortality", "novel strategies", "patient oriented", "patient oriented research", "physiologic model", "predictive modeling", "programs", "prospective", "research and development", "resp" ], "approved": true } }, { "type": "Grant", "id": "14763", "attributes": { "award_id": "1R01AG079230-01A1", "title": "The Effects of COVID-19 on the Well-being, Cognition and Mortality of Persons Living With Dementia", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Aging (NIA)" ], "program_reference_codes": [], "program_officials": [ { "id": 9749, "first_name": "PRISCILLA JOY", "last_name": "Novak", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-12-01", "end_date": "2028-11-30", "award_amount": 955699, "principal_investigator": { "id": 31463, "first_name": "MICHAEL D", "last_name": "HURD", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 515, "ror": "https://ror.org/00f2z7n96", "name": "RAND Corporation", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Although the prevalence of Alzheimer’s disease and related dementias (ADRD) has been decreasing, the COVID-19 pandemic may have halted or reversed that trend. This project will quantify the effects of the pandemic and of attendant public health and social measures on the cognitive status, mortality, and well-being of persons living with ADRD and of the older population in general. Persons living with dementia were especially vulnerable to COVID-19 because many were living in nursing homes, and even those residing in the community were disproportionately vulnerable because of caregivers coming to their homes. Further, those initially not living with dementia may have experienced accelerated cognitive decline because of COVID-19 infections, as well as due to disruption of daily routines, social isolation and stress. Subpopulations by race, ethnicity and socioeconomic status were impacted unequally. This project has three specific aims. The first is to use a new and updated model of cognition to estimate trends in ADRD prevalence, incidence, and mortality prior to the pandemic. We will use data from the Health and Retirement Study (HRS), a large, nationally representative, longitudinal survey of the U.S. population over age 50. The HRS has a wide range of information on cognitive abilities, mortality, dementia risks, and physical and mental health, but only a subsample of the HRS from the Aging, Demographic, and Memory Study (ADAMS) has a clinical assessment of dementia. In prior research, we used ADAMS to develop a model of the probability of dementia to estimate the cognitive status of the entire HRS sample. In this work, we will expand this model to estimate dementia incidence and mortality as well, and incorporate recently released data from the Harmonized Cognitive Assessment Protocol, further increasing precision so as to permit the study of changes in ADRD resulting from the pandemic in subpopulations, such as race and ethnicity, marital status, and socioeconomic status. Second, we will document changes associated with the pandemic in mortality, well-being, use of formal and informal care, and other outcomes. We will incorporate variation in state policies to assess their effect on individual outcomes. We will compare these effects among those who were living with dementia prior to the pandemic to those whose cognitive function was normal. We will use innovative models and data from various HRS supplements focusing on COVID-19 to estimate these effects with precision. Third, we will estimate the incidence of dementia and dementia mortality after the pandemic through 2026 and find the extent to which COVID-19 altered pre-pandemic trends. We will assess whether ADRD incidence differed by individual characteristics, such as geographic location, race, socioeconomic status, and living arrangements. The developed cognition measures will be made publicly available to enhance future research.", "keywords": [ "Acceleration", "Affect", "Age", "Aging", "Alzheimer&apos", "s disease model", "Alzheimer&apos", "s disease related dementia", "Anger", "COVID-19", "COVID-19 burden", "COVID-19 impact", "COVID-19 pandemic", "COVID-19 pandemic effects", "Caregivers", "Characteristics", "Classification", "Clinical assessments", "Cognition", "Cognitive", "Communities", "Data", "Data Collection", "Death Rate", "Dementia", "Disease", "Elderly", "Ethnic Origin", "Future", "General Population", "Geographic Locations", "Happiness", "Health", "Health Expenditures", "Health and Retirement Study", "Home", "Impaired cognition", "Incidence", "Individual", "Infection", "Interview", "Life", "Living Arrangement", "Long COVID", "Long-Term Care", "Longitudinal Surveys", "Marital Status", "Masks", "Measures", "Memory", "Mental Depression", "Mental Health", "Modeling", "Nature", "Neuropsychological Tests", "Nursing Homes", "Older Population", "Outcome", "Outcome Study", "Personal Satisfaction", "Persons", "Policies", "Population", "Prevalence", "Probability", "Protocols documentation", "Public Health", "Race", "Reporting", "Research", "Resources", "Respondent", "SARS-CoV-2 infection", "Sampling", "Sampling Studies", "Social isolation", "Socioeconomic Status", "Spouses", "Statistical Models", "Stress", "Unmarried person", "Update", "Vaccination", "Variant", "Work", "cognitive ability", "cognitive function", "cognitive testing", "data harmonization", "dementia risk", "demographics", "experience", "health data", "human old age (65+)", "infection rate", "informal care", "informant", "innovation", "insight", "interest", "mortality", "negative affect", "outcome disparities", "pandemic disease", "pandemic impact", "physical conditioning", "pre-pandemic", "response", "satisfaction", "sex", "social", "social stress", "trend" ], "approved": true } }, { "type": "Grant", "id": "14768", "attributes": { "award_id": "1R01DC020980-01A1", "title": "Mechanisms of anosmia and brain infection in a genetic mouse model of COVID-19", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Deafness and Other Communication Disorders (NIDCD)" ], "program_reference_codes": [], "program_officials": [ { "id": 6520, "first_name": "SUSAN L.", "last_name": "SULLIVAN", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-12-05", "end_date": "2028-11-30", "award_amount": 731611, "principal_investigator": { "id": 26334, "first_name": "Sarah E.", "last_name": "Millar", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 625, "ror": "https://ror.org/04a9tmd77", "name": "Icahn School of Medicine at Mount Sinai", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "Infection of the olfactory epithelium in COVID-19 patients is thought to underlie loss of smell (anosmia), a pathognomonic symptom that can be long-term in some patients, significantly affecting quality of life. The olfactory epithelium is also believed to be a major entry point for systemic SARS-CoV-2 infection, which can result in neurological as well as respiratory symptoms. Wild-type SARS-CoV-2 cannot bind the mouse ACE2 receptor, and existing human ACE2 (hACE2)-expressing mouse models either do not permit conditional analysis or do not confer severe illness after infection. Due to the lack of genetically manipulable models that display severe disease, the infected cell types responsible for acute and long-term anosmia, and the route(s) by which the virus penetrates the brain, have not been definitively identified. To address these gaps in knowledge and test cell type-specific requirements for COVID-19-related pathologies we generated conditional hACE2fl knockin mice that express hACE2 in similar cell types to humans. hACE2fl mice nasally inoculated with a high dose of wild-type SARS-CoV-2 display initial infection of olfactory epithelium and rapidly develop anosmia. This is followed by infection of neurons in the olfactory bulb and brain, which is associated with lethality and requires neuronal hACE2 expression. Importantly, specific destruction of olfactory epithelium via methimazole treatment prevents olfactory bulb and brain infection and lethality, identifying the olfactory epithelium as an essential gateway to CNS infection. hACE2fl mice inoculated with a low dose of wild-type SARS-CoV-2 show reversible disease and survive, but a subset displays a long-term decrease in odor sensitivity (hyposmia) like that observed in humans. We propose to use hACE2fl mice to provide definitive genetic evidence for cellular mechanisms of short- and long-term loss of smell and identify the pathways for brain infection during COVID-19. These studies are expected to complement existing descriptive human studies to identify causal pathogenic mechanisms and preventative and therapeutic targets. Three specific aims will be pursued: (i) define the cellular requirements for acute loss of smell; (ii) determine the mechanisms of long-term hyposmia; and (iii) uncover the cellular mechanisms of olfactory bulb and brain infection.", "keywords": [ "2019-nCoV", "ACE2", "ACTL6B gene", "ATAC-seq", "Ablation", "Acute", "Address", "Affect", "Anosmia", "Autopsy", "Binding", "Biological Assay", "Brain", "COVID-19", "COVID-19 patient", "COVID-19 susceptibility", "Cells", "Central Nervous System Infections", "Cerebrospinal Fluid", "Chromatin", "Complement", "Cranial Nerves", "Data", "Defect", "Dexamethasone", "Diffuse", "Disease", "Dose", "Functional disorder", "Gene Expression Profile", "Genetic", "Hamsters", "Human", "Impairment", "Infection", "Infiltration", "Inflammation", "Inflammatory", "Invaded", "K-18 conjugate", "Knock-in Mouse", "Knowledge", "Maintenance", "Methimazole", "Modeling", "Mus", "Natural regeneration", "Neurologic", "Neurologic Symptoms", "Neurons", "Nose", "Odors", "Olfactory Epithelium", "Pathogenicity", "Pathology", "Patients", "Pattern", "Penetration", "Phenotype", "Population", "Publishing", "Quality of life", "Respiratory Signs and Symptoms", "Route", "SARS-CoV-2 B.1.1.529", "SARS-CoV-2 infection", "Symptoms", "Testing", "Time", "Travel", "Viral", "Virus", "Visualization", "brain pathway", "cell type", "cribriform plate", "human data", "hyposmia", "interest", "lymphatic vessel", "mouse model", "neural", "olfactory bulb", "prevent", "receptor", "secondary infection", "single-cell RNA sequencing", "stem cells", "sustentacular cell", "therapeutic target" ], "approved": true } }, { "type": "Grant", "id": "15549", "attributes": { "award_id": "5R01MH135267-02", "title": "Maturation of Social and Non-Social Reward Processing in the Adolescent Amygdala and Orbitofrontal Cortex", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Mental Health (NIMH)" ], "program_reference_codes": [], "program_officials": [ { "id": 22777, "first_name": "Andrew Lee", "last_name": "Breeden", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-02-20", "end_date": "2028-11-30", "award_amount": 413001, "principal_investigator": { "id": 32088, "first_name": "Steve W. C.", "last_name": "Chang", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 31414, "first_name": "Katalin M", "last_name": "Gothard", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 438, "ror": "https://ror.org/03m2x1q45", "name": "University of Arizona", "address": "", "city": "", "state": "AZ", "zip": "", "country": "United States", "approved": true }, "abstract": "Adolescence is a time of substantial development attributed to the maturation of brain circuits that underlie the acquisition of new cognitive, emotional, and social skills. It is also a time of maximum vulnerability for mental disorders. In the past decade, the incidence of anxiety, depression, and suicide increased by ~60% in adolescents, remarkably more in females than in males. The social isolation during the COVID-19 pandemic added to the severity of the national and international statistics. To fully address the current youth mental health crisis, we need to understand how and why the dramatic reorganization of the adolescent brain contributes to the increased vulnerability to mental disorders. The studies proposed here rest on the assumption that the remodeling of the reward circuits of the brain creates the shared foundation of cognitive, affective, and social maturation during adolescence. Our multifaceted project addresses foundational gaps in our knowledge on how reward-driven motivational states inform adolescent behaviors such as risk-taking, pleasure-seeking, impulsivity, and a range of emotional responses to challenges of the social environment. We designed a within-subject, longitudinal study that spans the 2.5 - 3-year duration of adolescence in non-human primates. During this period, we will obtain repeated samplings of neurophysiological data recorded from the amygdala and orbitofrontal cortex in the context of the same behavioral tasks. In parallel, we will longitudinally monitor morphometric and microstructural changes in the gray and white matter of the brain through serial MRI scans, complemented by physical and hormonal measures of pubertal maturation. The three specific aims address the neural basis of three different aspects of reward processing in the subcircuit of the amygdala and orbitofrontal cortex. First, we will use a delay discounting task to determine the cellular and circuit level changes that underlie the increasing tolerance (or lack thereof) for delayed rewards. Second, we use a social reward-allocation task to test the neural underpinning of social reward processing in a self-oriented and an other-oriented social frame of reference. Finally, we will determine where and how social status is processed in the adolescent brain. Understanding social status relies on the ability to form abstract representations and is also a prerequisite for the successful integration of the individual into a hierarchical adult social group. The team, with combined expertise in human and non-human primate social behavior, neurophysiology, neuroimaging, and endocrinology, will apply conceptually and technically innovative approaches to generate unique and translational data, at both cellular and circuit levels, that account for the emerging cognitive, affective, and social skills acquired during adolescence.", "keywords": [ "Address", "Adolescence", "Adolescent", "Adolescent Behavior", "Adult", "Affective", "Amygdaloid structure", "Anxiety", "Area", "Behavior", "Behavior monitoring", "Behavioral", "Benefits and Risks", "Brain", "COVID-19 pandemic", "Cells", "Cognitive", "Data", "Decision Making", "Development", "Disparity", "Economics", "Education", "Emotional", "Emotional Bonds", "Endocrine", "Endocrinology", "Female", "Foundations", "Frequencies", "Glean", "Goals", "Hormonal", "Human", "Impulsivity", "Incidence", "Individual", "International", "Joints", "Knowledge", "Longitudinal Studies", "MRI Scans", "Macaca", "Measures", "Mental Depression", "Mental Health", "Mental disorders", "Modeling", "Monitor", "Monkeys", "Motivation", "Neurons", "Nutrition", "Outcome", "Partner in relationship", "Peer Group", "Performance", "Population", "Prefrontal Cortex", "Process", "Property", "Psychological reinforcement", "Puberty", "Race", "Rest", "Rewards", "Risk", "Risk Estimate", "Risk Taking", "Saccades", "Sampling", "Serial Magnetic Resonance Imaging", "Series", "Severities", "Social Behavior", "Social Environment", "Social Interaction", "Social isolation", "Social status", "Stress", "Suicide", "Testing", "Time", "United States National Institutes of Health", "Youth", "design", "discounting", "emotion regulation", "gaze", "gray matter", "innovation", "insight", "joint attention", "male", "multidisciplinary", "myelination", "neural", "neural circuit", "neuroimaging", "neurophysiology", "nonhuman primate", "peer", "pleasure", "response", "reward processing", "sex", "skill acquisition", "social", "social group", "social skills", "statistics", "white matter" ], "approved": true } }, { "type": "Grant", "id": "15555", "attributes": { "award_id": "5R01AI181955-02", "title": "Structural and functional definition of human astrovirus-receptor interactions", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 6817, "first_name": "Rodolfo M.", "last_name": "Alarcon", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-01-19", "end_date": "2028-11-30", "award_amount": 717595, "principal_investigator": { "id": 31411, "first_name": "Megan T", "last_name": "Baldridge", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 827, "ror": "", "name": "WASHINGTON UNIVERSITY", "address": "", "city": "", "state": "MO", "zip": "", "country": "United States", "approved": true }, "abstract": "Human astroviruses (HAstVs) are a global cause of pediatric gastroenteritis, and can cause disseminated infection in immunocompromised hosts. Seroprevalence studies indicate almost universal HAstV infection during childhood. Despite their clinical importance, HAstVs are highly understudied. Little is known about the host factors needed for infection or their mechanisms of viral entry into cells, and no proteinaceous viral receptor has been identified to date. Beyond providing critical insights into virus-host interactions, identification of host proteins sufficient and/or necessary for HAstV infection is key for creating small animal models permissive to infection and to revealing antiviral strategies to combat infection. Leveraging both genome-wide knock-out CRISPR and surfaceome-specific CRISPR activation screening, novel proteinaceous host receptors for HAstV were identified. These factors, neonatal Fc receptor (FcRn) and dipeptidyl peptidase 4 (DPP4), have also been implicated in viral infection for echovirus and coronavirus infection respectively. Both were confirmed as necessary for in vitro HAstV infection of Caco2 cells and as sufficient to permit HAstV infection of normally non-permissive human cells when overexpressed. Additionally, use of biolayer interferometry confirmed direct physical interactions between both FcRn and DPP4 with the HAstV capsid. These preliminary data serve as the critical foundation for the extensive structural and functional studies proposed here. In Aim 1, the specific protein domains and amino acid residues of FcRn and DPP4 that functionally interact with the HAstV capsid will be identified, as will the viral capsid residues critical for binding these host factors. Cryogenic electron microscopy will be leveraged to reveal how binding to these factors affects the HAstV virion. These genetic and biophysical analyses will provide much-needed insight into HAstV entry biology and form the basis of future pharmacological screens for identification of entry inhibitors. In Aim 2, permissive human intestinal enteroid cultures will be used to determine the necessity of identified entry factors for ex vivo HAstV infection. Blocking of infection via addition of soluble entry factors, anti-factor antibodies, inhibitors, and CRISPR-mediated disruption of factors in these cultures will be performed. Additionally, existing mouse models expressing human FcRn and DPP4 will be used to develop mice permissive to HAstV infection and to evaluate whether these factors are critical for murine astrovirus infection. These studies will reveal the species-specificity of receptor use and provide powerful new tools for study of HAstV pathogenesis and immune response as well as for preclinical testing of vaccines and antivirals. The use of numerous orthogonal approaches, including mechanistic studies of critical receptor domains, state-of-the-art structural techniques, and physiologically-relevant models, will yield a comprehensive picture of how these novel entry factors promote HAstV infection.", "keywords": [ "Affect", "Amino Acids", "Animal Model", "Anti-viral Agents", "Anti-viral Therapy", "Antibodies", "Astrovirus", "Binding", "Biology", "CRISPR screen", "CRISPR-mediated transcriptional activation", "Caco-2 Cells", "Capsid", "Cell Culture Techniques", "Cell Line", "Cells", "Childhood", "Clinical", "Clustered Regularly Interspaced Short Palindromic Repeats", "Colon Adenocarcinoma", "Complementary DNA", "Coronavirus Infections", "Cryoelectron Microscopy", "Data", "Development", "Dipeptidyl Peptidases", "Dipeptidyl-Peptidase IV", "Echo Viruses", "Echovirus Infections", "Ectopic Expression", "Encephalitis", "FDA approved", "Fc Receptor", "Foundations", "Future", "Gastroenteritis", "Gene Knock-Out Model", "Generations", "Genes", "Goals", "Human", "Immune response", "Immunocompromised Host", "In Vitro", "Individual", "Infection", "Infection prevention", "Innate Immune Response", "Integration Host Factors", "Interferometry", "Intestines", "Knock-in", "Knock-out", "Knowledge", "Maps", "Mediating", "Meningitis", "Middle East Respiratory Syndrome Coronavirus", "Modeling", "Molecular", "Mus", "Norovirus", "Pathogenesis", "Physiological", "Preclinical Testing", "Proteins", "RNA Viruses", "Research", "Resolution", "Role", "Rotavirus", "Seroprevalences", "Species Specificity", "Stomach", "Structure", "System", "Techniques", "Technology", "Tertiary Protein Structure", "Testing", "Transgenic Organisms", "Tropism", "Vaccines", "Viral", "Viral Gastroenteritis", "Virion", "Virus", "Virus Diseases", "Virus Receptors", "adaptive immune response", "biophysical analysis", "cell immortalization", "combat", "fighting", "flu", "genetic analysis", "genome-wide", "human model", "in vivo", "inhibitor", "innate immune pathways", "insight", "mortality", "mouse model", "neonatal Fc receptor", "novel", "overexpression", "permissiveness", "pharmacologic", "receptor", "receptor binding", "receptor expression", "receptor function", "reverse genetics", "screening", "tool", "vaccine evaluation", "virus host interaction" ], "approved": true } } ], "meta": { "pagination": { "page": 1384, "pages": 1419, "count": 14184 } } }