Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=5&sort=start_date
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=start_date", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1442&sort=start_date", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=6&sort=start_date", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=4&sort=start_date" }, "data": [ { "type": "Grant", "id": "7721", "attributes": { "award_id": "1ZIAAI000940-17", "title": "Pathogenesis of Tick-Borne Flavivirus Infections", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 1270472, "principal_investigator": { "id": 23513, "first_name": "Marshall", "last_name": "Bloom", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1540, "ror": "https://ror.org/043z4tv69", "name": "National Institute of Allergy and Infectious Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1540, "ror": "https://ror.org/043z4tv69", "name": "National Institute of Allergy and Infectious Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "While the COVID-19 pandemic, caused the novel -coronavirus SARS-CoV-2, ravages the world and has disrupted much biomedical research, infections with vector- borne flaviviruses continue their inexorable march as important emerging and re-emerging viral pathogens. The tick borne flaviviruses (TBFV) include tick borne encephalitis virus (TBEV), Omsk hemorrhagic fever virus, Kyasanur forest disease virus, Alkhurma hemorrhagic fever virus, Powassan/deer tick virus (POWV/DTV) and Langat virus (LGTV). TBFV are generally transmitted to humans by ixodid ticks, and cause a spectrum of disease ranging from mild febrile illness to encephalitis, meningitis or hemorrhagic fevers. In the US, the cases of all tick-borne infections are increasing dramatically. POWV/DTV are the only autochthonous TBFV and case reports of serious illness and death are also on the increase. Importantly, POWV/DTV is transmitted by Ixodes scapularis ticks, the same vector that transmits the agent of Lyme disease, Borrelia burgdorferi, as well as several other emerging agents. Thus, a comprehensive evaluation of various tick-borne infections is needed to fully unravel the biology of the TBFV. These pathogens will continue to pose public health problems even in the face of the coronavirus pandemic. The mosquito borne flaviviruses include West Nile virus (WNV), Japanese encephalitis virus (JEV), dengue virus (DEN) and yellow fever virus (YFV). The dramatic and ongoing pandemic attributed to the MBFV Zika virus is important because of its capacity to cause a severe congenital Zika disease as well an ever increasing spectrum of neurological syndromes in adults. Our current investigations are focused on the TBFV, but studying the biology of TBFV will illuminate the biology of other vector borne viruses. The research in our laboratory employs virology, immunology, entomology, advanced imaging techniques, genomics, cell biology, molecular biology, and vector biology. We study LGTV, a naturally attenuated member of the TBFV that can be safely studied at Biosafety Level-2 (BSL-2) as well as the virulent autochthonous BSL-3 POWV/DTV. These viruses are not Select Agents which greatly facilitates research studies. In addition, we have also continued to study the BSL2 MBFV, Zika virus. With the persistent emergence of Zika in the western hemisphere, similar avenues of inquiry are being explored for that vexatious pathogen. TBFV biology in ex vivo cultures of I. scapularis organs. Infection in ticks is patently a critical feature of TBFV biology, but it is woefully understudied. Transmission of TBFV from the bite an Ixodes scapularis tick can occur in less than 15 minutes; thus virus biology in salivary glands (SG) is of considerable interest. In the past year, we extended our studies of ex vivo SG cultures to include male ticks. The feeding behavior of male ticks differs from that of females and their possible role in pathogen transmission unclear. We demonstrated that TBFV initiate a productive infection in male tick SG cultures, inferring that male ticks may also play a role in virus transmission. Confocal microscopy of SG cultures infected with a GFP-expressing TBFV revealed that not all granular acini support infection. This finding suggested that virus may target specific types of acini and specific cell types in SG. Thus, SG cultures likely provide a convenient and controlled system in which to look for genes associated with POWV replication and to assay antiviral countermeasures. Another aspect of this project involves identifying transcripts in SG cultures of female ixodid ticks that promote infection or are proviral. Since SG are the final barrier to transmission from the tick, identification of such genes would be of considerable interest, because proviral transcripts might serve as potential targets for countermeasure development. To date, four proviral transcripts have been identified via RNA interference assays in flavivirus-infected salivary gland cultures. Current ongoing research will finalize these RNA interference assays using salivary gland cultures from female ixodid ticks. Extending this work to confirm a proviral function of these transcripts in infected whole ticks would be logical. Finally, pathogen-tick interaction studies need to be confirmed in intact ticks, and furthermore emerging evidence from other groups indicates that the physiology of replete and partially fed ticks differs from unfed ticks. For example, TBFV grows to higher levels in fed ticks versus unfed ticks. Thus, it will be key to elucidate TBFV infection in ticks during various stages of blood feeding. We are approaching this issue by studying tick attachment, TBFV uptake and reproduction during blood feeding by means of small capsules with silicone-based membrane submerged in blood.. We have optimized female tick attachment using this setup and have confirmed partial feeding within these ticks. Ongoing work is confirming virus uptake using this method and characterizing virus replication as the ticks feed. This strategy will be very useful for various applications dealing with pathogen-tick studies during feeding. Since it does not involve live mammals as a target, the method will also be convenient for studying high consequence pathogens. This work was done by post-doctoral fellow Dr. Jeffrey Grabowski and post-baccalaureate trainee Luke Kendall. Microbial interactions within the microbiome of the tick Ixodes scapularis Studies indicate that B. burgdorferi can infect over 70% of I. scapularis ticks in some regions of the U.S., while POWV/DTV infects less than 5%. Similarly, the bacterial endosymbiont Rickettsia buchneri can achieve infection rates of 100% of the I. scapularis populations in some U.S. regions. Although there may be multiple reasons to explain this range of infection rates, one intriguing possibility is that ticks infected with one microbe may be less susceptible to infection by a second agent. Dr. Phillip Stewart joined BVBVS last year, bringing a wealth of experience in B. burgdorferi and other tick bacteria. Thus, we were able to establish a new project to probe for interactions (beneficial or antagonistic) between microbial species inhabiting I. scapularis. As this tick species is the leading vector of disease in the U.S., identifying such interactions may highlight methods to disrupt the infectious cycle of pathogens. Progress in this project was also halted by COVID-19, and results are minimal so far. However, the specific aims of this project are: 1.) Establish new techniques to study potential interactions between the microbial symbionts of the tick I. scapularis. We have adapted existing in vitro cell culture systems and in vivo animal models to sequentially introduce specific microbial species and directly assess their impact on the ability of a second agent to infect and persist. For the predominant symbiont R. buchneri, we are establishing methods to eliminate this endosymbiont from I. scapularis individuals, which will allow us to compare infection rates of both B. burgdorferi and POWV in these dysbiosed ticks. 2.) Identify the mechanisms of interactions between these microbes. Molecular pathogenesis of TBFV infections. In the past year Dr. Dylan Flather continued to employ genome wide loss of function studies to identify cellular genes that modulate TBFV infections, notably the autochthonous BSL3 TBFV POWV/DTV. Haploid mutagenized or Genome-Scale CRISPR Knock-Out (GecKO) lentiviral transduced cell pools, which contain individual knockouts of nearly all non-essential human genes, were infected with POWV. Deep sequencing of surviving cell populations allowed for the identification of deleted genes that are putative pro-viral host factors, as cells lacking these genes persist in cell culture following infection. Genes identified in this manner fell into", "keywords": [ "2019-nCoV", "Acinus organ component", "Adult", "Alkhurma Virus", "Animal Model", "Antiviral Agents", "Arthropods", "Attenuated", "Bacteria", "Basic Science", "Biological Assay", "Biology", "Biomedical Research", "Bite", "Black-legged Tick", "Blood", "Borrelia burgdorferi", "COVID-19", "COVID-19 pandemic", "Case Study", "Cell Culture System", "Cell Culture Techniques", "Cells", "Cellular biology", "Cessation of life", "Clustered Regularly Interspaced Short Palindromic Repeats", "Confocal Microscopy", "Coronavirus", "Deer Tick", "Dengue Virus", "Development", "Disease", "Disease Vectors", "Encephalitis", "Entomology", "Evaluation", "Experimental Models", "FDA approved", "Feeding behaviors", "Female", "Fever", "Flavivirus", "Flavivirus Infections", "Genes", "Genomics", "Haploidy", "Human", "Image", "Imaging Techniques", "Immunology", "In Vitro", "Individual", "Infection", "Integration Host Factors", "Investigation", "Ixodes", "Japanese encephalitis virus", "Knock-out", "Kyasanur Forest disease virus", "Laboratories", "Langat virus", "Legal patent", "Lyme Disease", "Mammals", "Membrane", "Meningitis", "Methods", "Microbe", "Molecular", "Molecular Biology", "Neurologic", "Omsk hemorrhagic fever virus", "Organ", "Pathogenesis", "Pharmaceutical Preparations", "Physiology", "Play", "Population", "Postdoctoral Fellow", "Powassan virus", "Public Health", "RNA Interference", "Reporting", "Reproduction", "Research", "Resources", "Rickettsia", "Role", "Salivary Glands", "Silicones", "Syndrome", "System", "Techniques", "Tick-Borne Encephalitis Virus", "Tick-Borne Infections", "Ticks", "Transcript", "Viral", "Viral Hemorrhagic Fevers", "Virulent", "Virus", "Virus Replication", "West Nile virus", "Work", "Yellow fever virus", "ZIKA", "ZIKV disease", "Zika Virus", "base", "capsule", "cell type", "cellular transduction", "deep sequencing", "endosymbiont", "experience", "feeding", "genome-wide", "hemorrhagic fever virus", "in vivo", "infection rate", "interest", "lentivirally transduced", "loss of function", "male", "member", "microbial", "microbiome", "microorganism interaction", "mosquito-borne", "novel", "novel coronavirus", "pandemic disease", "pathogen", "pathogenic virus", "research study", "symbiont", "tick feeding", "tick-borne", "transmission process", "uptake", "vector", "vector-borne", "viral transmission", "virology" ], "approved": true } }, { "type": "Grant", "id": "7767", "attributes": { "award_id": "1ZICDK071013-13", "title": "Human Energy and Body Weight Regulation Core", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 869835, "principal_investigator": { "id": 23570, "first_name": "Kong", "last_name": "Chen", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1600, "ror": "https://ror.org/00adh9b73", "name": "National Institute of Diabetes and Digestive and Kidney Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1600, "ror": "https://ror.org/00adh9b73", "name": "National Institute of Diabetes and Digestive and Kidney Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "The Core continues to be a part of the Metabolic Clinical Research Unit (MCRU), which was established at NIH in 2007 under the first NIH Strategic Plan for Obesity Research (http://www.obesityresearch.nih.gov/strategic-plan). It is design to conduct research to identify potential causes and evaluate treatments of obesity. Currently 1/3 of the adult US population is obese and another 1/3 are overweight. Obesity is a major cause of diabetes, cardiovascular disease, and some cancers, yet our understanding of obesity physiology is rudimentary. The obesity epidemic has continued unabatedthe need for rigorous and properly controlled metabolic research is even more important. At the NIH, much of the Intramural clinical research is conducted on the MCRU that consists of the 5SW-N (inpatient) unit, 5SW-S (day hospital), and 7SW-S whole room calorimetry suites, which includes a special room with a DXA body composition scanner, and Bod Pod, an exercise testing room, portable activity measurements, and highlighted by the three customized whole-room indirect calorimeters (respiratory chambers) as the key components of the Core function. Due to the COVID-19 global pandemic that closed the MCRU on March 15, only to gradually returning in limited capacity starting in July. As a result, our census and services rendered were negatively impacted: energy expenditure by respiratory chambers (91), resting energy expenditure by metabolic carts (112), graded-exercise tests (27), experimental food behavior tests (237), and body composition (101 DXA, 15 Bod Pod). The Core continues to support 29 clinical protocols and protocols from 14 different IC's of the NIH. We are planning to begin several new clinical protocols in late 2020 to early 2021 (if the MRCU is back to normal operational status), including an exercise intervention trial in post-hospitalized COVID patients (with NIH Clinical Center Rehabilitation Department), a protocol to test anti-Inflammatory effects of time-restricted feeding in patients with inflammatory psoriasis (with NHLBI), a pilot study to measure acute effects of medium chain triglyceride nutritional ketosis on Parkinsons Disease symptoms and biomarkers (with NIMH), another study with NIMH to measure sleep, energy expenditure, and circadian rhythm in patients with bipolar disorders, and a randomized clinical trial to measure early metabolic effects of two new anti-HIV drug combinations in healthy volunteers. Research highlights in FY20: 1.\tThere are currently more than 30 research laboratories on 5 continents which have whole-room indirect calorimeters for human metabolism studies. The types of studies range from comparison of respiratory calorimetry measures across populations to use for assessment of exercise physiology, activity monitoring, sleep, and effects of diet and pharmacologic and environmental interventions. The limited availability is due to expense and the technical expertise required to support their operation and continued maintenance. However, there are currently no accepted standards for calibration and operation, quality control, protocol design, signal processing, or data reporting. As a result, comparing results between laboratories is often difficult, and the ability to perform multicenter trials is limited. We organized and lead an international panel of room indirect calorimeter experts from the US, Europe, and Asia from 2019-20 with the goal to establish the standards for reporting 1) technical specifications; 2) data reduction, and analytical approaches; 3) performance standards including accuracy, precision, stability, and repeatability; 4) elements of study design, including the basis for power analyses, inclusion/exclusion criteria, and appropriate considerations of potential confounders (e.g., pre-study dietary intake); and 5) outcome measures. The panel agreed this effort would improve the ability to compare data among studies, educate and guide new researchers to the field, and facilitate preparations and reviews of new publications. The manuscript outlining the Room Indirect Calorimetry Operating and Reporting Standards, version 1.0 (RICORS 1.0) provides guidance to ensure consistency and facilitate meaningful comparisons and reproducibility of human energy metabolism studies across publications and clinical sites. It is published and chosen as the Editors Choice selection in the 2020 September issue of Obesity. 2.\tWe published several papers in FY 20 on the changes of sleep and physical activity patterns and their associations with mental and physical health parameters in Icelandic adolescents at 15 and 17 years of age, all stemming from a long-term collaboration project with a team of researchers at the University of Iceland. We found an alarming percentage of these adolescents did not have sufficient sleep during most school nights (averaging about 6 hours/night), and screen time was associated with the sleep variability, which together with physical inactivity, were associated with less favorable metabolic profiles such as total and trunk fat percentages. Together, these findings support the idea that both sufficient amount of sleep, physical activity, and perhaps regular schedules are important for the health of adolescents. 3.\tWe have been studying childhood obesity since the establishment of the Core. We continue to contribute to the studies with Dr. Jack Yanovskis research group from NICHD and Dr. Lauren Shomaker (previously a postdoc with Dr. Yanovski, now an associate professor at Colorado State University) and publish results in the area of adolescent weight and insulin resistance and depression. For example, we found that, in adolescent girls at-risk for T2D with moderately elevated depression, randomization to cognitive-behavioral therapy (CBT) produced greater decreases in depression at post-treatment and greater decreases in fasting/2-h insulin at 1 year, compared to health education. We then examined whether decreasing depression explained intervention effects on body composition and insulin outcomes and found an indirect effect of CBT on decreased 1-year fasting insulin via decreases in depression during treatment, among adolescents with more elevated baseline depression. These findings suggest that insulin resistance and anxiety symptoms are associated and decreasing elevated depression may be one mechanism in the targeted prevention of T2D in at-risk adolescents.", "keywords": [ "17 year old", "Acute", "Adolescent", "Adult", "Aftercare", "Anti-HIV Agents", "Antiinflammatory Effect", "Area", "Asia", "Back", "Biological Markers", "Bipolar Disorder", "Body Composition", "Body Temperature", "Body Weight", "COVID-19", "Calibration", "Calorimetry", "Cardiovascular Diseases", "Censuses", "Circadian Rhythms", "Clinical Protocols", "Clinical Research", "Cognitive Therapy", "Collaborations", "Colorado", "Custom", "Data", "Data Analyses", "Data Reporting", "Diabetes Mellitus", "Diet", "Dietary intake", "Drug Combinations", "Dual-Energy X-Ray Absorptiometry", "Elements", "Energy Metabolism", "Ensure", "Europe", "Exclusion Criteria", "Exercise Physiology", "Exercise Test", "Fasting", "Fatty acid glycerol esters", "Female Adolescents", "Food", "Goals", "Health education", "Heart Rate", "Hour", "Human", "Iceland", "Indirect Calorimetry", "Inflammatory", "Inpatients", "Insulin", "Insulin Resistance", "International", "Intervention Trial", "Ketosis", "Laboratories", "Laboratory Research", "Lead", "Length of Stay", "Maintenance", "Malignant Neoplasms", "Manuscripts", "Measurement", "Measures", "Medium chain triglycerides", "Mental Depression", "Mental Health", "Metabolic", "Modification", "Monitor", "Multicenter Trials", "National Heart Lung and Blood Institute", "National Institute of Child Health and Human Development", "National Institute of Mental Health", "Non-Insulin-Dependent Diabetes Mellitus", "Nutritional", "Obesity", "Obesity Epidemic", "Outcome", "Outcome Measure", "Outpatients", "Overweight", "Paper", "Parkinson Disease", "Patients", "Pattern", "Performance", "Pharmacology", "Physical activity", "Physiology", "Pilot Projects", "Population", "Postdoctoral Fellow", "Preparation", "Prevention", "Protocols documentation", "Psoriasis", "Publications", "Publishing", "Quality Control", "Randomized", "Randomized Clinical Trials", "Regulation", "Rehabilitation Centers", "Reporting", "Reproducibility", "Research", "Research Design", "Research Personnel", "Rest", "Risk", "Schedule", "Schools", "Services", "Sleep", "Strategic Planning", "Symptoms", "Technical Expertise", "Testing", "Time-restricted feeding", "United States National Institutes of Health", "Universities", "Weight", "adolescent health", "analytical method", "anxiety symptoms", "associated symptom", "behavior test", "clinical center", "clinical research site", "coronavirus disease", "data red" ], "approved": true } }, { "type": "Grant", "id": "7775", "attributes": { "award_id": "1ZIACL090070-01", "title": "Clinical and Molecular Features of Coronavirus Disease 2019", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 0, "principal_investigator": { "id": 23580, "first_name": "Daniel S", "last_name": "Chertow", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1620, "ror": "", "name": "CLINICAL CENTER", "address": "", "city": "", "state": "", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1620, "ror": "", "name": "CLINICAL CENTER", "address": "", "city": "", "state": "", "zip": "", "country": "United States", "approved": true }, "abstract": "Project 1: We have established a cohort of 40 patients with COVID-19 who received extra-corporeal membrane oxygenation (ECMO) in collaboration with the University of Maryland. We have collected daily plasma and peripheral blood mononuclear cell samples and intermittent respiratory samples (e.g., tracheal aspirate, bronchoalveolar lavage) from these patients. Matched demographic and clinical data from these patients have also been collected. Initial analyses of this cohort are ongoing. We have performed detailed postmortem examinations of 21fatal COVID-19 cases. Approximately 50 tissues per patient will be studied for viral RNA quantification and detection of live virus, histopathology, and a subset of tissues will be prepared for transmission electron microscopy for submicron visualization of SARS-CoV-2-cell interactions and tissue pathology. Leukocytes have been isolated from multiple tissue types for immunophenotyping and functional analyses. These studies are ongoing.", "keywords": [ "2019-nCoV", "Acute", "Aspirate substance", "Autopsy", "Bronchoalveolar Lavage", "COVID-19", "Caring", "Cell Communication", "Cessation of life", "Clinical", "Clinical Data", "Cohort Analysis", "Collaborations", "Critical Illness", "Data", "Detection", "Diagnostic radiologic examination", "Disease", "Economics", "Extracorporeal Membrane Oxygenation", "Failure", "Functional disorder", "Goals", "Health", "Histopathology", "Human", "Immune response", "Immunology", "Immunophenotyping", "Individual", "Laboratories", "Leukocytes", "Maryland", "Molecular", "Multicenter Studies", "Natural History", "Pathology", "Patients", "Peripheral Blood Mononuclear Cell", "Plasma", "Recovery", "Research", "Sampling", "Therapeutic", "Tissues", "Transmission Electron Microscopy", "Universities", "Vaccine Design", "Virus", "Visualization", "clinical care", "cohort", "improved", "longitudinal analysis", "multidisciplinary", "novel", "pandemic disease", "pathogen", "pathogenic virus", "respiratory", "submicron", "viral RNA", "virology" ], "approved": true } }, { "type": "Grant", "id": "7744", "attributes": { "award_id": "1ZIAAI001298-01", "title": "Paramyxoviruses as Vaccine Vectors Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 787601, "principal_investigator": { "id": 23540, "first_name": "Ursula", "last_name": "Buchholz", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1540, "ror": "https://ror.org/043z4tv69", "name": "National Institute of Allergy and Infectious Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1540, "ror": "https://ror.org/043z4tv69", "name": "National Institute of Allergy and Infectious Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "There are no vaccines to protect against SARS-CoV-2 infection and COVID-19 disease caused by SARS-CoV-2. Effective vaccines are urgently needed. Paramyxovirus vectors expressing an immunogenic version of the SARS-CoV-2 S protein would provide novel live vaccines for intranasal administration, designed to be highly attenuated in humans while maintaining a high level of immunogenicity at the primary sites of infection of SARS-CoV-2. A major emphasis is being put on developing paramyxovirus vector vaccines that should not be restricted by pre-existing immunity in the human population. These viral vectors are designed to replicate in the superficial layers of the respiratory epithelium, inducing local mucosal and systemic innate immunity, virus-neutralizing serum antibodies, and CD8+ and CD4+ T cells. Intranasal paramyxovirus vector vaccines would provide systemic and local protection in the respiratory tract, the primary site of SARS-CoV-2 infection, and, similar to other live viral vaccines, are expected to rapidly induce immunity following a single dose of vaccine. Large quantities of vaccine doses could be generated rapidly.", "keywords": [ "2019-nCoV", "African Green Monkey", "Antibodies", "Attenuated", "Attenuated Vaccines", "CD4 Positive T Lymphocytes", "CD8B1 gene", "COVID-19", "Cattle", "Development", "Disease", "Disease Outbreaks", "Dose", "Human", "Immunity", "Immunization", "Infection", "Intranasal Administration", "Modeling", "Mucous Membrane", "Natural Immunity", "Para-Influenza Virus Type 3", "Paramyxovirus", "Population", "Proteins", "Respiratory System", "SARS coronavirus", "Serum", "Severe Acute Respiratory Syndrome", "Site", "Structure of respiratory epithelium", "Vaccines", "Viral Vaccines", "Viral Vector", "Virus", "base", "conjunctiva", "design", "immunogenic", "immunogenicity", "neutralizing antibody", "nonhuman primate", "novel", "pandemic disease", "pathogen", "response", "vaccine candidate", "vector", "vector vaccine" ], "approved": true } }, { "type": "Grant", "id": "7760", "attributes": { "award_id": "1ZIAEY000184-38", "title": "Genetic, Cellular and Molecular Mechanisms in Autoimmunity to Retina", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Eye Institute (NEI)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 3720450, "principal_investigator": { "id": 23559, "first_name": "Rachel R.", "last_name": "Caspi", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1611, "ror": "https://ror.org/03wkg3b53", "name": "National Eye Institute", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1611, "ror": "https://ror.org/03wkg3b53", "name": "National Eye Institute", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "AUTOIMMUNE AND INFLAMMATORY RESPONSES AFFECTING THE RETINA Most of these studies utilized mouse models of autoimmune uveitis developed in our laboratory, (i) experimental autoimmune uveitis (EAU) induced in mice by immunization with the retinal antigen (Ag) IRBP, and (ii) spontaneous uveitis in R161H mice that express a transgenic T cell receptor (TCR) specific for the IRBP epitope encoded by residues 161-180. 1)\tCommensal flora is necessary for development of spontaneous uveitis, but not of immunization-induced EAU. WT mice treated with antibiotics (ABX) before birth, developed full blown EAU. However, ABX starting a week before EAU challenge, afforded measurable protection. We found that long term ABX depletes intraepithelial lymphocytes (IEL), which are known to be microbiota-dependent. These cells appear to inhibit activation of uveitis-inducing R161H lymphocytes. We hypothesize that they may have a regulatory role in uveitis, which is reversed by long-term antibiotic treatment due to depletion of IEL. (Salvador et al., in preparation). 2)\tThe role of IL-17 and IFN-g cytokines in pathogenesis and regulation of uveitis is being studied using both the classical and the spontaneous uveitis models, with emphasis on the balance between Th1 and Th17 responses, and their control by T-regulatory (Treg) cells. a)\tUsing mice deficient in both IL-17 and IFN-, we demonstrated that disease is still induced, but is now mediated by distinct effector cytokine profile. GM-CSF appears to be a critical pathogenic cytokine, which may drive disease in the absence of both IFN- and IL-17 (S Bing et al, J. Autoimmun. 2020). b)\tWe revealed a novel regulatory pathway elicited by IL-17, a major proinflammatory cytokine. By binding to the IL-17R on activated T cells, IL17 elicits production of IL-24, which suppresses production of other Th17-related cytokines, including, importantly, GM-CSF. We speculate that the loss of this regulatory pathway in uveitis patients treated with anti-IL-17 neutralizing antibody (Secukinumab) may underlie the ineffectiveness of this therapy (WP Chong et al., Immunity 2020). 3)\tVitamin (VitA) derivatives are necessary for functional activation of immune cells (published literature). We previously demonstrated the importance of Vitamin A (VitA) and its metabolite, retinoic acid, in ocular immune privilege. Using mice made VitA deficient (VAD), we found that T cell effector function that was acquired before onset of VAD, is maintained in the VAD host. These findings may have clinical implications in regions where dietary VitA is limiting. (Horai, Zhou et al, in preparation). 4) \tLaquinimod is an aryl hydrocarbon receptor (AHR) agonist. We found that it has strong protective effects in the induced model of EAU, and marked protective effects in the spontaneous uveitis model in R161H mice. Its action is by modulating multiple inflammatory and anti-inflammatory cytokines, and may affect composition of gut flora, which in turn affects development of disease. (Xu et al, and Tang et al, in preparation) 5) Tristetraprolin (TTP) is an inducible endogenous anti-inflammatory protein that controls expression of cytokines. In collaboration with P. Blackshear, NIEHS, we studied induced mutant mice that overexpress TTP. We found that these mice are resistant to EAU, have reduced proinflammatory responses and enhanced regulatory responses. The primary effect seems to be on T cell priming, by affecting antigen-presenting cells. (Xu et al., in revision). 6) \"Licensing\" of T cells for pathogenicity: It has been demonstrated that activated T cells specific to retina or brain infused into a new host first settle in peripheral tissues (spleen, lung) where they become \"licensed\" to invade the target tissue. We are currently examining whether the gut, which affects uveitis via its resident commensal flora, can serve as a licensing site that might be important in pathogenesis (Salvador et al., in preparation). EFFECTS OF INNATE IMMUNE RESPONSES ON OCULAR IMMUNITY AND AUTOIMMUNITY: The innate immune system can be involved in tissue pathology directly, or indirectly by affecting adaptive immunity. In collaboration with Dr. Holly Rosenzweig, OHSU, Portland, OR, we found that, unexpectedly, NOD2, which is usually thought of as an inflammation-promoting receptor, limits autoimmunity to the neuroretina. This involves downregulation of IL-17 production from T cells via a novel, T cell intrinsic pathway, and not through conventional APC priming. This study uncovers a hitherto unrecognized role for Nod2 as an inherent genetic modifier of T cell function in uveitis.. (Nature Communications, 2020 in press). THE OCULAR SURFACE MICROBIOME AND MUCOSAL IMMUNE RESPONSES AT THE OCULAR SURFACE Mucosal sites such as the intestine, oral cavity, nasopharynx, and vagina all have associated commensal flora. The surface of the eye is also a mucosal site, but presence of ocular surface microbiome was contentious. Previously, we isolated and purified a candidate ocular commensal, Corynebacterium mastitidis (C. mast). This organism elicits a commensal-specific IL-17 response from T cells in the ocular mucosa, tuning local host defense to afford protection from infectious pathogenic organisms. 1) \tWe are examining the molecular sensors of C. mast in T cells. Data suggest that V4 T cells respond to C. mast mainly via their TCR, whereas V6 T cells respond through innate receptors such as TLR2, and are highly dependent on IL-1. DC are involved in this response in a dual capacity as APC that present C. mast components and as a source of IL-1. To elicit an efficient Th17 response, TLR2 appears to be required not only in DC (where it contributes to IL-1 induction), but also in T cells. The mechanism of intrinsic T cell requirement for TLR2 is being investigated (Zhu et al. and Xu et al., in preparation). 2) \tAnother direction of study examines commensal-elicited responses in an immunologically abnormal host, mouse as well as human. In collaboration with the group of Dr. Warren Strober (NIAID) who developed knock-in mice expressing a gain-of-function mutation in the NLRP3 inflammasome gene, and Dr. Raphaela Goldbach-Mansky who treats patients with NLRP3 inflammasome related diseases, we have obtained evidence to suggest that an ocular surface commensal can elicit ocular surface inflammation, thus acting as a pathobiont. We are currently characterizing the local ocular immune response and the ocular surface microbiome in the mouse model and in patients with NLRP3 inflammasome mutations at the single-cell level (Siak, St. Leger et al., in preparation). This may have implications for understanding and treatment of the characteristic ocular inflammation in patients with NLRP3-related diseases. COVID-19 related: EFFECTS OF THE MICROBIOME ON CYTOKINE STORM IN A \"HUMANIZED\" MOUSE MODEL. COVID-19 patients' morbidity and mortality is being attributed in large measure to elicitation of a cytokine storm due to an excessive immune response triggered by the virus. The project uses immunodeficient NSG mice reconstituted with human leukocytes and treated with broad spectrum antibiotics to eliminate endogenous microbiota, to examine whether its presence affects the cytokine storm elicited by GVH (chronic) or by OKT3 antibody (acute). Preliminary data indicate that there are measurable effects on immune and physiological parameters relating to both responses. This may suggest that the status of the commensal microbiome is a factor cytokine storm response of COVID-19 patients. (Mattapallil et al., in progress).", "keywords": [ "Acute", "Affect", "Agonist", "Animal Model", "Anti-Inflammatory Agents", "Antibiotic Therapy", "Antibiotics", "Antibodies", "Antigen-Presenting Cells", "Arrestins", "Aryl Hydrocarbon Receptor", "Autoimmune Responses", "Autoimmunity", "Binding", "Bioinformatics", "Birth", "Brain", "COVID-19", "Cell physiology", "Cells", "Characteristics", "Chronic", "Clinical", "Collaborations", "Communication", "Corynebacterium", "Data", "Development", "Diet", "Disease", "Down-Regulation", "Epitopes", "Equilibrium", "Experimental Models", "Eye", "Genes", "Genetic", "Goals", "Granulocyte-Macrophage Colony-Stimulating Factor", "Holly", "Homeostasis", "Host Defense", "Human", "IL17 gene", "Immune", "Immune response", "Immunity", "Immunization", "Immunologics", "Immunology", "Immunotherapy", "Inflammasome", "Inflammation", "Inflammatory", "Inflammatory Response", "Innate Immune Response", "Innate Immune System", "Interferon Type II", "Interferons", "Interleukin-1", "Interleukin-17", "Intestines", "Invaded", "Knock-in Mouse", "Laboratories", "Lead", "Leg", "Leukocytes", "Licensing", "Literature", "Lung", "Lymphocyte", "Measurable", "Measures", "Mediating", "Modeling", "Molecular", "Morbidity - disease rate", "Mucosal Immune Responses", "Mucous Membrane", "Muromonab-CD3", "Mus", "Mutant Strains Mice", "Mutation", "Nasopharynx", "National Institute of Allergy and Infectious Disease", "National Institute of Environmental Health Sciences", "Nature", "Oral cavity", "Organism", "Pathogenesis", "Pathogenicity", "Pathology", "Pathway interactions", "Patients", "Peripheral", "Physiological", "Preparation", "Process", "Production", "Proteins", "Publishing", "Regulation", "Regulatory Pathway", "Regulatory T-Lymphocyte", "Resistance", "Retina", "Role", "Site", "Source", "Spleen", "Surface", "T cell response", "T-Cell Receptor", "T-Lymphocyte", "TIS11 protein", "TLR2 gene", "Therapeutic", "Tissues", "Transgenic Organisms", "Tretinoin", "Uveitis", "Vagina", "Virus", "Vision", "Vitamin A", "Vitamins", "adaptive immunity", "autoimmune uveitis", "clinical material", "commensal microbes", "cytokine", "cytokine release syndrome", "effector T cell", "gain of function mutation", "gut microbiota", "humanized mouse", "immune activation", "ineffective therapies", "interstitial retinol-binding protein", "intraepithelial", "microbiome", "microbiota", "mortality", "mouse model", "mucosal site", "neutralizing antibody", "novel", "ocular surface", "over" ], "approved": true } }, { "type": "Grant", "id": "7699", "attributes": { "award_id": "1ZIAES103345-01", "title": "SARS-CoV-2 Studies", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Environmental Health Sciences (NIEHS)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 438205, "principal_investigator": { "id": 23493, "first_name": "DOUGLAS", "last_name": "BELL", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1605, "ror": "https://ror.org/00j4k1h63", "name": "National Institute of Environmental Health Sciences", "address": "", "city": "", "state": "NC", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1605, "ror": "https://ror.org/00j4k1h63", "name": "National Institute of Environmental Health Sciences", "address": "", "city": "", "state": "NC", "zip": "", "country": "United States", "approved": true }, "abstract": "Smoking, Immune Senescence and COVID-19 morbidity. The general approach is to prospectively establish a bank of cryopreserved PBMCs from smokers and nonsmokers before any COVID-19 exposure and use CyTOF to analyze detailed immune profiles. Subjects will return for second post-COVID-19 pandemic visit to provide a second blood sample for analysis. The focus is primarily on immune profiles compared with COVID-19 incidence (or levels of morbidity) in smokers. As seen in Figure 2, there is a large variance in CD16+CD8+ T cell frequency among smokers. We hypothesize that senescent CD16+CD8+ T cells will be higher in smokers who develop COVID-19 or who have more severe morbidity. Specific Aims and Experimental Plans Specific Aim 1. Establish CyTOF immune profiles in 60 smokers and 60 matched nonsmokers who are COVID-19 negative and will be followed up on and recalled after the COVID-19 pandemic has subsided. Specific Aim 2. Compare immune profiles determined from a post-COVID-19 visit to the pre-COVID-19 negative sample. COVID-19 Diagnostics. Aim 1. Develop cDNA library methods for SARS-CoV-2 and host cells suitable for Next Generation sequencing.", "keywords": [ "2019-nCoV", "Bar Codes", "Blood specimen", "CD8-Positive T-Lymphocytes", "COVID-19", "COVID-19 pandemic", "Cells", "Communicable Diseases", "Cryopreservation", "Diagnostic", "Disease Outbreaks", "FCGR3B gene", "Frequencies", "Genetic Transcription", "Goals", "Guide RNA", "Healthcare Systems", "Immune", "Immune System Diseases", "Incidence", "Infection", "Methods", "Morbidity - disease rate", "Peripheral Blood Mononuclear Cell", "Predisposition", "Premature aging syndrome", "Regulatory T-Lymphocyte", "Sampling", "Screening procedure", "Severe Acute Respiratory Syndrome", "Smoker", "Smoking", "T-Lymphocyte Subsets", "Viral", "Visit", "cDNA Library", "follow-up", "high risk", "indexing", "mortality", "next generation sequencing", "non-smoker", "prospective", "response", "screening", "senescence" ], "approved": true } }, { "type": "Grant", "id": "7698", "attributes": { "award_id": "1ZICAI001226-03", "title": "Center for Human Immunology", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 3460631, "principal_investigator": { "id": 23492, "first_name": "Yasmine", "last_name": "Belkaid", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1540, "ror": "https://ror.org/043z4tv69", "name": "National Institute of Allergy and Infectious Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1540, "ror": "https://ror.org/043z4tv69", "name": "National Institute of Allergy and Infectious Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "In response to the SARS-CoV-2 pandemic we have made the technologies and platforms at CHI available for characterization of COVID-19 patient samples, as a priority ahead of our ongoing collaborative studies. By early April we had completed adaptation of our transcriptomic and flow cytometry platforms, and operating procedures, to begin analysing peripheral blood from Covid-19 patients. CHI began receiving samples from Northern Italy and CITE-Seq was performed for more than 100 samples in close collaboration with the Tsang lab. BCR sequencing and scATAC seq was performed for a subset of these, and proteomic analysis was obtained for all of the samples by outsourcing this work at SomaLogic. 27-color flow cytometry phenotyping was also performed by CHI to validate the novel CITE-seq platform. Further, CHIs automated pipeline was used to isolate high quality RNA from PAXgene samples of 200 Covid-19 samples, to be used for both RNA-Seq at CHI as well as distribution to the Goldbach-Mansky lab. Together these efforts have contributed to initial immune characterization of acutely infected Covid-19 patients. We hope these platforms can now be applied to new cohorts becoming available which are able to address questions such as variation in the outcomes of infection. In addition to this COVID work CHI has continued to advance its previous studies that comprise 25 active collaborations across 8 Institutes and the Clinical Center. These are divided into 3 stages: initiation/sample collection (12 studies), assay (8 studies), and analysis/write up (5 studies). These all comprise multi-modal high-dimensional immune phenotyping of primary human samples. The current studies include characterizing immune changes in vaccine trials (malaria, HSV), clinical intervention trials (lupus, CHAPLE), and cohort studies of rare diseases (mitochondrial dysfunction). One of the new studies added is an exciting collaboration with Kevin Hall at NIDDK to characterize immune differences after periods of highly controlled diet changes. The monoclonal antibody therapy study of CHAPLE disease patients, with Mike Lenardo, is an example of how high dimensional phenotyping can lead to better understanding of patient pathology, and may inform use of a nascent therapy. The proteomic changes we observed give basic biology insight into, in this case, CD55 function and the mechanisms of complement inhibition, and this work is under review at Nature Immunology. Studies published this year included an integrated proteomic and cellular phenotyping analysis of maternal peripheral blood in longitudinally sampled human pregnancies, and characterization of changes in peripheral blood during treatment of healthy subjects with statins, and obese individuals undergoing a clinical trial of colchicine treatment. To support CHIs mission we continue to develop wet-lab and computational infrastructure. For single cell sequencing technologies using the 10x platform, we have expanded the number of protein antigens measured in CITE-Seq, and developed scATAC-seq approaches with greater throughput and lower cost. CITE-Seq, in particular, led to a high-profile finding characterizing variation in baseline immune states that predicts immune responses (see section Scientific Advances). For flow cytometry, on a new Cytek Aurora we have validated a 27 color cytometry for broad immune phenotyping, as well as a 33 color T cell focused panel run after PMA stimulation to detect cells primed for production of characteristic cytokines or transcription factors. For flow cytometry analysis we are applying methods to enable conventionally gated populations to be recognized and interrogated using high dimensional parameters, to help overcome the difficulties of interpreting unbiased clustering of high dimensional data. For mass cytometry analysis we are finalising a package that uses high dimensional observations to discriminate only the subset of cells that respond in ex vivo stimulation assays, such as our mass cytometry assay that quantifies phosphorylation of 10 intracellular proteins, in addition to 20 cell phenotype markers, in response to 12 in vitro stimulation conditions. CHI also provides fee-for-service access to assays not otherwise accessible to NIH researchers. The SomaLogic proteomic assay has been run for over 1000 samples, for 8 investigators, in the last year. This included human and murine samples from serum, plasma, cerebrospinal fluid, bronchioalveolar lavage fluid, and tissue homogenates. We continue to monitor alternative platforms and have run tests on O-Link that is offering increasingly high parameter antibody based analysis, although currently plan to transition our SomaLogic platform from the current 1.3k antigen panel to an analysis of 4.5k antigens.", "keywords": [ "2019-nCoV", "Acute", "Address", "Antibodies", "Antigens", "Behavior", "Biological", "Biological Assay", "Biology", "Bronchoalveolar Lavage", "COVID-19", "Cells", "Cerebrospinal Fluid", "Characteristics", "Clinical", "Clinical Trials", "Cohort Studies", "Colchicine", "Collaborations", "Color", "Complement", "Computer Analysis", "Computer Models", "Coupled", "Cytometry", "Data", "Development", "Diet", "Disease", "Fee-for-Service Plans", "Flow Cytometry", "Goals", "Health", "Health Services Accessibility", "Human", "Immune", "Immune response", "Immunity", "Immunologic Monitoring", "Immunology", "Immunotherapy", "In Vitro", "Individual", "Infection", "Institutes", "Intervention", "Intervention Trial", "Italy", "Laboratories", "Lead", "Leadership", "Link", "Liquid substance", "Lupus", "Malaria", "Measures", "Methods", "Mission", "Modeling", "Monitor", "Monoclonal Antibody Therapy", "Mus", "National Institute of Allergy and Infectious Disease", "National Institute of Diabetes and Digestive and Kidney Diseases", "Nature", "Obesity", "Outcome", "Outsourcing", "Pathology", "Patients", "Phenotype", "Phosphorylation", "Plasma", "Population", "Pregnancy", "Procedures", "Production", "Proteins", "Proteomics", "Publishing", "RNA", "Rare Diseases", "Research Personnel", "Resources", "Review Committee", "Running", "Sampling", "Scientific Advances and Accomplishments", "Serum", "Services", "Simplexvirus", "System", "T-Lymphocyte", "Technology", "Testing", "Tissues", "Training", "United States National Institutes of Health", "Vaccination", "Variant", "Work", "Writing", "base", "clinical application", "clinical center", "cohort", "collaborative approach", "computer infrastructure", "coronavirus disease", "cost", "cytokine", "data mining", "data modeling", "design", "high dimensionality", "insight", "microbiome", "microbiome research", "microbiota", "mitochondrial dysfunction", "multidimensional data", "multimodality", "novel", "pandemic disease", "peripheral blood", "phenotypic biomarker", "programs", "recruit", "response", "sample collection", "single cell sequencing", "tool", "transcription factor", "transcriptome sequencing", "transcriptomics", "vaccine trial" ], "approved": true } }, { "type": "Grant", "id": "7717", "attributes": { "award_id": "1ZIAAG000778-04", "title": "The role of immune cells in Alzheimer's disease", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Aging (NIA)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 528921, "principal_investigator": { "id": 23510, "first_name": "Arya", "last_name": "Biragyn", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1613, "ror": "https://ror.org/049v75w11", "name": "National Institute on Aging", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1613, "ror": "https://ror.org/049v75w11", "name": "National Institute on Aging", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "The role of B cells in Alzheimer's disease (AD) remains poorly understood even though we and others showed their benefit as producers of antibody that help to eliminate neurotoxic beta-amyloid depositions (Ab plaques) (Olkhanud et al, Vaccine, 2011). About 6 years ago, we have hypothesized that B cells could also be promoting AD because they upregulate expression of inflammatory factors together with the onset of AD in 3xTgAD mice. We tested this possibility in 3 different mouse models of AD, such as 3xTgAD, APP/PS1 and 5xFAD mice, utilizing complementing experimental strategies. First, we generated B-cell deficient (BKO) mice that develop AD in young and old age, 2xTgAD and 3xTgAD mice by crossing BKO mice with 2xTgAD and 3xTgAD mice, respectively. The loss of B cells in these mice almost completely reversed the AD symptoms despite expression of AD-promoting transgenes. Compared to age/sex-matched B-cell sufficient littermates, 2xTgAD/BKO and 3xTgAD/BKO mice exhibited reduced anxiety and improved memory deficits. Both 2xTgAD/BKO and 3xTgAD/BKO mice contained significantly fewer Ab-plaques in the brain subiculum than their age- and sex-matched littermates. The over activated microglia, another hallmark of AD pathology, in both mice without B cells was also markedly reduced. To confirm this finding, we also transiently depleted B cells from the circulation of mice with AD, such as 3xTgAD, APP/PS1 and 5xFAD mice, by injecting CD20-targeting antibody. The B-cell depletion indeed significantly delayed AD symptoms in all three types of mice. Overall, for the first time we demonstrate that B cells play pathogenic role in AD and, importantly, their transient depletion from the circulation can delay AD onset. The paper, which we recently submitted for publication, came back for revision. Due to the COVID-19 quarantine, we had to terminate experiments and cull essential AD mice, precluding a proper addressing the editor and reviewers comments. We therefore expect to finalize this paper by middle of 2021. Despite this, we have played the key roles in successful completion of 2 papers from our collaborators on Ad and AD-like symptoms in Down syndrome.", "keywords": [ "APP-PS1", "Address", "Age", "Aging", "Alzheimer&apos", "s Disease", "Alzheimer&apos", "s disease model", "Alzheimer&apos", "s disease pathology", "Antibodies", "Anxiety", "B-Lymphocytes", "Back", "Blood Circulation", "Brain", "COVID-19", "Cells", "Complement", "Disease", "Down Syndrome", "Exhibits", "Goals", "Immune", "Inflammatory", "MS4A1 gene", "Memory impairment", "Microglia", "Mus", "Onset of illness", "Paper", "Pathogenicity", "Play", "Publications", "Published Comment", "Quarantine", "Role", "Symptoms", "Testing", "Therapeutic", "Time", "Transgenes", "Vaccines", "abeta deposition", "experimental study", "improved", "mouse model", "neurotoxic", "sex" ], "approved": true } }, { "type": "Grant", "id": "7707", "attributes": { "award_id": "1ZIADK075104-08", "title": "Understanding protein folding, evolution and function via molecular simulation", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 866673, "principal_investigator": { "id": 23501, "first_name": "Robert", "last_name": "Best", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1600, "ror": "https://ror.org/00adh9b73", "name": "National Institute of Diabetes and Digestive and Kidney Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1600, "ror": "https://ror.org/00adh9b73", "name": "National Institute of Diabetes and Digestive and Kidney Diseases", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "The project has addressed the following areas in the past year: 1. Studies of SARS-Cov2 Main Protease. In collaboration with John Louis (NIDDK), we have investigated the autoprocessing mechanism of the SARS-Cov2 Main Protease. A reaction coordinate was developed that can describe the conformational change between the native protease structure and a putative transient state required for protease autoprocessing, a key step for viral replication. Simulations show that this state is only slightly higher in free energy than the native state and should be populated on a microsecond to millisecond time scale, making the proposed autoprocessing mechanism extremely plausible. Future work will investigate this mechanism further and whether it can be exploited to design novel inhibitors for SARS proteases (R. Best). 2. Association of highly charged intrinsically disordered proteins. Recent work in collaboration with Ben Schuler's single molecule FRET group in Zurich has shown that high affinity disordered complexes of proteins or proteins and nucleic acids may be ubiquitous in cell nuclei. We are seeking to develop a predictive model for the affinity and structure of these complexes, initially via molecular simulation, but then via a semi-empirical theory fitted to experimental data collected in the Schuler lab (M. Ivanovic). 3. Development of coarse-grained models for complex coacervation of intrinsically disordered proteins with single- and double-stranded nucleic acids. Going beyond the 1:1 complexes studied in project 1, it is also possible for oppositely charged macromolecules such as proteins and DNA or RNA to undergo complex coacervation, forming a separate phase with high macromolecular density, under the correct conditions. Such a phenomenon may provide a physical basis for the formation of some of the membraneless organelles observed in the cell nucleus. We have developed a coarse-grained simulation model of protein-nucleic acid interactions, and used it to study the ordering induced on formation of the condensed phase. Future work will include improving the transferability of the model to different sequences and making it more sensitive to sequence-specific effects (K. Lebold). 4. Development of transferable sequence-specific models for liquid-liquid phase separation (LLPS) of intrinsically disordered proteins. We had previously shown that a simple coarse-grained model could be useful for modelling qualitative effects on protein liquid-liquid phase separation, the basis for formation of many membraneless organelles within cells. However, this model was not very predictive of which proteins would undergo phase separation. We have therefore undertaken a comprehensive refitting of the energy function in order to describe both the properties of isolated disordered chains and also those of proteins which are known to phase separate. The inclusion of the latter data set results in a great improvement of the overall accuracy of the model, owing to some of the effects which are important for driving LLPS not being well represented in the database of isolated (non phase-separating) proteins. This work is currently in preparation for publication (T. Dannenhoffer-Lafage). 5. All-atom simulations of protein phase separation and complex coacervation. Using time obtained on the Anton supercomputer, together with novel multiscale simulation methodology, we have performed the first all-atom simulations of a protein-rich phase representative of those obtained in protein LLPS. We have characterized the interactions driving formation of this phase, the partitioning of ions into the dense phase, and the dynamics of proteins within the phase - paper currently under review. We now intend to apply similar methodology to the more challenging problem of coacervation of oppositely charged proteins, in order to elucidate the interactions responsible for stabilizing these phases (M. Ivanovic). 6. Co-translational protein folding. In collaboration with Gunnar von Heijne, we have used our previously developed model for co-translational folding on the ribosome to investigate more directly the relationship between the forces arising from the folding nascent chain and the yield of full length protein obtained in arrest peptide experiments. We also devised a method for obtaining these forces directly from experiment by using a series of different arrest peptides with the same protein constructs (5). In a second collaboration with the group of Sander Tans, we are using our coarse-grained co-translational folding model to understand the effects of the ribosome on the folding and unfolding rates of ADR1a in the ribosome exit tunnel, as probed by single molecule force and fluorescence spectroscopy. We have recently started a new collaboration with Alexey Amunts in Stockholm to interpret their cryo-EM results on mitochondrial ribosomes (R. Best, P. Tian). 7. Using sequence-based energy functions to describe protein fitness landscapes and for protein design. Building on our success in describing the fitness landscape of a single fold using coevolutionary models, we are seeking to design sequences which can fold into two different structures as envisaged in our recent theoretical work (7). We are collaborating with Susan Marqusee's group to test some of these ideas (P. Tian). We are also looking to develop similar ideas to identify proteins which naturally switch folds (such as RfaH), using sequence information (L. Frechette). 8. Modelling sensitivity of single molecule experiments to protein folding transition paths using molecular simulations. Recent single molecule fluorescence experiments have been able to detect transition paths between folded and unfolded states of proteins by combining photon by photon detection with sophisticated maximum likelihood analysis algorithms. However, it is not clear how the inferred transition path durations relate to the actual folding transition path lengths, since they cannot be independently measured. We have used simulations as a model to generate coarse-grained folding trajectories for two proteins (alpha3D, protein G), in which we can unambiguously assign transition paths. We then generated synthetic photon trajectories from these simulations and analyzed them in the same way as the experimental data. We found that the experimentally inferred transition path durations are of the right magnitude, but systematically shorter than the true durations. Beyond current analysis methods, we are also testing the feasibility of obtaining information besides just the length of the transition path, i.e. transition path \"shape\", from this type of experiment, using synthetic data generated from our simulations (G. Taumoefolau). 9. Using transition-path sampling to study the mechanism and rate of assembly of transmembrane protein dimers, as represented by Glycophorin A. We have used our force field developed to best reproduce the stability of Glycophorin A in POPC membranes to study the dynamics of protein association using enhanced sampling methods (transition-path sampling) (4). We find that association occurs via an intermediate in which non-native interactions are initially formed between the helices, followed by a second step driven by native interactions. The same approach should be applicable to study oligomerization of other transmembrane domains. (J. Domanski). Group members or jointly supervised external collaborators involved in each project are listed at the end of each section.", "keywords": [ "2019-nCoV", "Address", "Affinity", "Algorithmic Analysis", "Area", "Automobile Driving", "Base Sequence", "Cell Nucleus", "Cells", "Charge", "Collaborations", "Complex", "Cryoelectron Microscopy", "Cytoplasmic Granules", "DNA", "Data", "Data Set", "Databases", "Development", "Disease", "Evolution", "Fluorescence", "Fluorescence Spectroscopy", "Free Energy", "Future", "G-substrate", "GYPA gene", "Goals", "Grain", "Integral Membrane Protein", "Ions", "Length", "Liquid substance", "Measures", "Membrane", "Membrane Proteins", "Methodology", "Methods", "Mitochondria", "Modeling", "Molecular", "Molecular Conformation", "National Institute of Diabetes and Digestive and Kidney Diseases", "Nucleic Acids", "Organelles", "Paper", "Peptide Hydrolases", "Peptides", "Phase", "Photons", "Preparation", "Property", "Protein Dynamics", "Protein Engineering", "Proteins", "Publications", "RNA", "Reaction", "Refit", "Resolution", "Ribosomes", "Sampling", "Series", "Severe Acute Respiratory Syndrome", "Shapes", "Structure", "Supervision", "Testing", "Time", "Transmembrane Domain", "Virus Replication", "Work", "amyloid fibril formation", "density", "design", "dimer", "experimental study", "fitness", "improved", "inhibitor/antagonist", "interest", "macromolecule", "member", "millisecond", "models and simulation", "non-Native", "novel", "photon-counting detector", "predictive modeling", "protein aggregation", "protein complex", "protein folding", "protein function", "protein misfolding", "simulation", "single molecule", "single-molecule FRET", "success", "supercomputer", "theories", "time use" ], "approved": true } }, { "type": "Grant", "id": "7782", "attributes": { "award_id": "1ZIABC011872-02", "title": "PSMA-PET Imaging of High Risk Prostate Cancer-Cures", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Cancer Institute (NCI)" ], "program_reference_codes": [], "program_officials": [], "start_date": null, "end_date": null, "award_amount": 1116551, "principal_investigator": { "id": 23588, "first_name": "peter L", "last_name": "choyke", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1601, "ror": "", "name": "DIVISION OF BASIC SCIENCES - NCI", "address": "", "city": "", "state": "", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1601, "ror": "", "name": "DIVISION OF BASIC SCIENCES - NCI", "address": "", "city": "", "state": "", "zip": "", "country": "United States", "approved": true }, "abstract": "This study has now started accrual. It is a multi-institutional trial involving the use of PSMA PET/CT in high risk patients. The PSMA PET agent, F18 DCFPyl, is provided to sites by Progenics. The American College of Radiology will assist in archiving imaging and pathology. Approximately 4 patients have been accrued at the NCI site to date and accrual was interrupted by the COVID pandemic. To date we have seen excellent performance of the PSMA PET agent and the surgery has been successfully performed without incident.", "keywords": [ "American College of Radiology", "FOLH1 gene", "Funding", "Interruption", "Malignant neoplasm of prostate", "Operative Surgical Procedures", "PET/CT scan", "Pathology", "Patients", "Performance", "Positron-Emission Tomography", "Protocols documentation", "Recurrence", "Scanning", "Site", "Testing", "Time", "coronavirus disease", "high risk", "image archival system", "pandemic disease", "prostate cancer risk" ], "approved": true } } ], "meta": { "pagination": { "page": 5, "pages": 1442, "count": 14420 } } }